JP4843988B2 - Polysulfone hollow fiber membrane blood purifier - Google Patents

Description

  The present invention relates to a blood purifier that is excellent in selective permeability in blood purification treatment for removing water, has little change in performance over time, and has high storage stability.

  In blood purification therapy for the treatment of renal failure, natural materials such as cellulose, cellulose diacetate, cellulose triacetate, synthetic polymers such as polysulfone, Blood purifiers such as hemodialyzers, hemofilters or hemodialyzers using a dialysis membrane using a polymer such as methyl methacrylate or polyacrylonitrile or an ultrafiltration membrane as a separating material are widely used. In particular, blood purifiers that use hollow fiber membranes as separation materials are used in the dialyzer field because of their advantages such as reducing the volume of extracorporeal circulating blood, increasing the efficiency of removing substances in the blood, and increasing productivity when producing blood purifiers. Is highly important.

  Among the above-mentioned membrane materials, polysulfone-based resins having high water permeability are attracting attention as the best match with the progress of dialysis technology. However, when a semi-permeable membrane is made of a single polysulfone, the polysulfone resin is hydrophobic, so it has poor affinity with blood and causes an airlock phenomenon. Can not.

As a method for solving the above-described problems, a method has been proposed in which a hydrophilic polymer is blended with a polysulfone-based resin to form a film, thereby imparting hydrophilicity to the film. For example, a method of blending a polyhydric alcohol such as polyethylene glycol is disclosed (for example, see Patent Documents 1 and 2).
JP-A-61-232860 JP 58-114702 A

Moreover, the method of mix | blending polyvinylpyrrolidone is disclosed (for example, refer patent document 3, 4).
Japanese Patent Publication No. 5-54373 Japanese Examined Patent Publication No. 6-75667

As a measure for solving the above problems, a method using polyvinylpyrrolidone as a hydrophilic polymer has attracted attention from the viewpoint of safety and economy. However, in the hydrophilization technique by blending polyvinyl pyrrolidone, there arises a problem that polyvinyl pyrrolidone is eluted and mixed into purified blood during dialysis. When elution of the hydrophilic polymer increases, the hydrophilic polymer, which is a foreign substance taken up by the human body, increases in the body during long-term dialysis and may cause side effects and complications. Therefore, the elution amount of the polyvinyl pyrrolidone and the like is determined by the dialysis-type artificial kidney device manufacturing approval standard. In the dialysis type artificial kidney device manufacturing approval standard, it is quantified by UV absorbance. A technique is disclosed in which the effect of elution control is determined according to the dialysis artificial kidney device manufacturing approval standard. (For example, see Patent Documents 5 to 7). Patent Document 8 discloses a semipermeable membrane for blood treatment in which the elution amount of hydrophilic polymer from the semipermeable membrane is 10 ppm or less. This document discloses a technique for suppressing elution of a hydrophilic polymer from a semipermeable membrane for blood treatment, but it is a process related to deterioration / degradation of the hydrophilic polymer over time, which extends to storage of a hollow fiber membrane. No mention is made of the effects of hydrogen oxide.
Japanese Patent No. 3314861 JP-A-6-165926 JP 2000-350926 A JP 2001-170171 A

  As a result of detailed studies on the elution behavior of the polyvinyl pyrrolidone, the present inventors have found that in the extract extracted by the test method defined by the above dialysis-type artificial kidney device manufacturing approval standards, It was found that hydrogen peroxide that cannot be measured was included. When hydrogen peroxide is present in the blood purifier and in the selectively permeable separation membrane, for example, it promotes oxidative degradation of polyvinylpyrrolidone, and the storage stability that the elution amount of the polyvinylpyrrolidone increases when the hollow fiber membrane bundle is stored. I found out that it gets worse. However, in the above-mentioned patent document, a technique for suppressing elution of hydrophilic polymer from the blood treatment semipermeable membrane is disclosed, but deterioration of the hydrophilic polymer over time extends to storage of the hollow fiber membrane. -No mention is made of the influence of hydrogen peroxide on decomposition.

  Furthermore, in the prior art disclosed in Patent Documents 5 to 8 described above, all have been evaluated for specific portions of the hollow fiber membrane bundle. Actually, when the treatment such as drying the hollow fiber membrane bundle is performed in the blood purifier assembly or the like, it has been found that the above-mentioned elution amount largely fluctuates in the hollow fiber membrane bundle due to the influence of the fluctuation of the drying conditions. However, the evaluation of only the specific part cannot answer the high safety requirement. In particular, when hydrogen peroxide as clarified by the present inventors is present in a specific part of the hollow fiber membrane bundle, the deterioration reaction of the hollow fiber membrane bundle material is started from that point and propagates to the entire hollow fiber membrane bundle. Therefore, it is necessary to ensure that the amount of the hollow fiber membrane bundle used in the blood purification device in the length direction is below a certain amount over the entire region.

  On the other hand, in a blood purifier, radiation irradiation treatment may be performed for the purpose of crosslinking or sterilizing polyvinyl pyrrolidone in the selectively permeable hollow fiber membrane filled in the blood purifier. However, when irradiated, modification may be caused to a part of the hydrophilic polymer in addition to the crosslinking reaction and sterilization effect. That is, it reacts with water or oxygen in the treatment atmosphere to generate an unstable functional group or partial structure in an oxidized state, or a new functional group is generated by hydrolysis. Even if the content of the hydrophilic polymer in the entire membrane is small, most of it is concentrated on the surface of the polysulfone-aggregated particles by phase separation, so these effects on blood are not negligible. As a result, the anti-thrombogenicity of the membrane may be reduced due to physicochemical changes in these modified parts. In addition, the denaturation continued during long-term storage after irradiation, and the antithrombogenicity could be lowered before actual use.

For example, as a method for solving the above problems, in a film irradiated with radiation, if the carboxyl group content and the peroxide content in the film are controlled within a certain range, the film is excellent in antithrombogenicity and stored for a long time. However, a technique capable of maintaining an antithrombotic state is disclosed (see Patent Document 9).
JP 2000-135421 A

  However, the blood purifier of the technique disclosed in the above-mentioned patent document is a method applied to a so-called wet type blood purifier irradiated with water in a state of water filling. The wet type blood purifier is naturally heavy due to water filling, and is inconvenient to transport and handle. In cold regions, the water filled in the blood purifier freezes in the severe cold season and the hollow fiber membrane ruptures. And problems such as damage. In addition, there are high cost factors such as preparation of a large amount of sterilized water. Moreover, in order to make the hollow fiber membrane both moist and easy for bacteria to propagate, it is conceivable that the bacteria will proliferate during a short period after packaging until sterilization. As a result, the blood purifier manufactured in this manner is not preferable because it takes a long time to obtain a completely sterilized state, which leads to higher cost or safety. This technique is irradiated with radiation in the presence of a radical scavenger, and has a problem that an operation for washing and removing the radical scavenger in advance is necessary when used for blood purification. Therefore, the establishment of a so-called dry-type blood purifier loaded with a dry permeable hollow fiber membrane and capable of avoiding the above-described problems even when irradiated with radiation in the absence of a radical scavenger is strongly desired. Has been.

  In addition, when the blood purifier is used as a dialyzer for an artificial kidney, it is necessary to perform a complete sterilization process before use. For the sterilization treatment, formalin, ethylene oxide gas, high-pressure steam sterilization, γ-ray radiation or electron beam irradiation sterilization methods, and the like are used, each exhibiting a unique effect. Among these, the sterilization method by radiation or electron beam irradiation is adopted as a preferable sterilization method because it can process the object to be processed in a packaged state and has an excellent sterilization effect.

However, it is known that hollow fiber membranes used in blood purifiers and adhesives used for fixing the hollow fiber membranes are deteriorated by radiation irradiation, and a method of sterilizing while preventing deterioration. Has been proposed. For example, a method for suppressing deterioration of the hollow fiber membrane by γ-ray irradiation by making the hollow fiber membrane in a wet state with a saturated moisture content or higher is disclosed. (For example, refer to Patent Document 10). However, this method has the same problem as that of Patent Document 9.
Japanese Patent Publication No.55-23620

As a method of avoiding the above-mentioned wet state and suppressing deterioration due to radiation irradiation, a method of irradiating a hollow fiber membrane with a sterilizing protective agent such as glycerin or polyethylene glycol and irradiating with γ rays in a dry state is disclosed. (For example, refer to Patent Document 11). However, since this method contains a protective agent in the hollow fiber membrane, it is difficult to keep the water content of the hollow fiber membrane low, and the problem of deterioration of the protective agent due to γ-ray irradiation and the protective agent immediately before use are difficult. There was a problem that it took time and effort to clean and remove.
JP-A-8-168524

As a method for solving the above problems, in a dialyzer containing a semipermeable membrane, 100% or more of water is held with respect to the weight of the semipermeable membrane, and the inside of the dialyzer is made an inert gas atmosphere. A method of manufacturing a dialyzer that performs gamma irradiation is disclosed. (For example, refer to Patent Document 12). However, there is no mention of the characteristics that the hollow fiber membrane should have before irradiation with radiation and the influence on the priming property of the hollow fiber membrane due to the irradiation of radiation.
JP 2001-170167 A

Further, as a method for solving the above problems, a method of sterilizing by irradiating with radiation in a state where the moisture content of the hollow fiber membrane is 5% or less and the relative humidity near the hollow fiber membrane is 40% or less is disclosed. Yes. (For example, refer to Patent Document 13). In the method, the above-mentioned problems have been solved, and the ultraviolet absorbance at a wavelength of 220 to 350 nm measured in accordance with the dialysis membrane elution test of the dialysis artificial kidney device manufacturing approval standard satisfies the standard value of 0.1 or less. ing. However, in Patent Document 13, there is no mention of the influence of the oxygen concentration around the hollow fiber membrane at the time of sterilization, changes in the amount of eluate eluted over time after sterilization, and the like.
JP 2000-288085 A

Moreover, in the method of performing sterilization by γ-ray irradiation, a method is disclosed in which the insolubilized component of the membrane material is achieved to 10 wt% or less by performing γ-ray irradiation in a state where the moisture content of the hollow fiber membrane is 10 wt% or less. . (For example, refer to Patent Document 14). The patent document discloses that the amount of the hydrophilic polymer per 1 m ^{2 of the} liquid contact side area of the membrane extracted with a 40% ethanol aqueous solution can be 2.0 mg / m ² or less. However, in this patent document as well, the influence of oxygen concentration around the hollow fiber membrane when γ-irradiation is performed, the elution amount of the eluate after sterilization treatment over time or the effect on priming properties by sterilization treatment, etc. There is no mention about.
JP 2001-205057 A

Further, as a method for avoiding deterioration of the base material of the medical device due to oxygen, a method of sealing the medical device together with an oxygen scavenger with a packaging material made of an oxygen-impermeable material and performing radiation irradiation is known. Is also disclosed. (For example, refer to Patent Documents 15 to 17).
Japanese Patent Application Laid-Open No. 62-74364 JP-A-62-204754 WO98 / 58842 publication

  As the deterioration due to the radiation irradiation using the oxygen scavenger described above, Patent Document 15 shows that odor is generated, Patent Document 16 shows that the strength of the base material and dialysis performance are lowered, and Patent Document 17 shows that the strength of the base material is reduced and aldehyde. Although the occurrence of sucrose has been described, there is no mention of the increase in the amount of extract described above. Moreover, although the oxygen concentration in the packaging bag at the time of radiation irradiation is described, nothing is mentioned about the importance of moisture in the hollow fiber membrane.

  Furthermore, as the material of the packaging bag used in the method of radiation sterilization in the above-mentioned system using an oxygen scavenger, the importance of gas, especially oxygen impermeability is described, but with respect to humidity permeability, Not mentioned.

Also disclosed is a method of radiation sterilizing a liquid processing device filled with a film protective agent in a wet or semi-wet shape in an inert gas atmosphere (see, for example, Patent Document 18). In this patent document, a method of using an oxygen scavenger as an achievement means for creating an inert gas atmosphere is disclosed. In addition, water is listed as a film protective agent. On the other hand, although the lower limit of the moisture content in the semi-wet state is not mentioned, the problem to be solved by the invention is that “glycerin, physiological saline or water oozes out and the inside wall of the liquid processor and the inside of the packaging bag There was a problem of adhering to the hand and adhering to the hand during the operation of the liquid processing apparatus, ”suggesting that the water content is higher than the saturated water content. Therefore, it can be regarded as a technique having the same problem as in Patent Document 10.
JP-A-8-280795

In order to maintain the sterilization effect for a long time, a method of sterilizing a dry type hollow fiber membrane blood purifier by vacuum packaging and irradiating with γ rays has been disclosed (for example, see Patent Document 19). However, no consideration is given to the deterioration of the hollow fiber membrane during γ-ray irradiation or storage. In addition, no mention is made regarding the moisture content of the hollow fiber membrane.
JP 2001-149471 A

Further, it is disclosed that the amount of peroxide in the hollow fiber membrane is increased by irradiating the dried hollow fiber membrane with γ rays compared to the irradiation in the wet state. No mention is made of a method for suppressing the formation of peroxides during irradiation (see, for example, Patent Document 20).
JP 2000-135421 A

  Furthermore, in the method of suppressing the elution of polyvinylpyrrolidone in the production of the selectively permeable hollow fiber membrane used for blood purification treatment as described above, or the method of irradiating radiation such as γ rays for sterilization, the hollow fiber at the time of irradiation Although some have been disclosed regarding the moisture content of the membrane and the irradiation atmosphere conditions, mention is made of the properties that the hollow fiber membrane should have before irradiation and the influence of the irradiation on the priming property of the hollow fiber membrane. Not.

Further, a liquid separation membrane package and a storage method in which a liquid separation membrane used for various industrial water treatments or the like is packaged with a film having a specific composition in which air permeability is suppressed are disclosed (for example, patent documents). 21). The method relates to a package in a wet state in which a package is filled with deoxygenated water having a specific dissolved oxygen concentration, and a storage method.
JP 2004-195380 A

Moreover, in the drying of the hollow fiber membrane bundle, a method of drying by irradiating with microwaves is disclosed. However, in this patent document, the generation of hydrogen peroxide during drying and the storage stability of the dried hollow fiber membrane bundle are disclosed. No consideration is given to sex (for example, see Patent Documents 22 to 25).
JP 2003-175320 A JP 2003-175321 A JP 2003-175322 A JP 2004-305997 A

On the other hand, in recent years, also in blood purifiers intended to remove blood waste products by extracorporeal circulation, downsizing and higher performance of blood purifiers are required. For example, according to the artificial kidney performance evaluation standard established by the Japanese Society for Artificial Organs, blood side flow rate 200 ml / min, heparinized bovine blood (hematocrit 30%, total protein concentration 6.5 g / dl) as blood side solution, Disclosed is a hollow fiber membrane blood purifier having a β2-microglobulin clearance of 73.2 ml / min to 93.0 ml / min in an in vitro system measured under conditions of a water removal amount of 10 ml / min and a membrane area of 1.5 m ^2. (See Patent Document 26).
Japanese Patent No. 3257999

  The blood purifier disclosed in Patent Document 26 has a high clearance of β2-microglobulin and responds to the above demand for higher performance. However, in the blood purifier disclosed in Patent Document 26, the pressure on the dialysate side is higher than the blood side pressure on the upstream side of the dialysate, and the dialysate side pressure is set on the blood side on the downstream side of the dialysate. The above-described high performance is achieved by a so-called internal filtration method in which the pressure difference between the dialysate side and the blood side is increased before and after the dialysate flow direction, which is lower than the pressure of the dial. Therefore, it is necessary to increase the pressure at the inflow of dialysate and increase the flow control ability. For this reason, the capability including the reliability of the flow control mechanism (for example, a pump, a circuit, a valve, a sensor, etc.) in the blood purification system becomes high, and there is a problem that the entire system becomes expensive. In addition, the method for increasing the pressure difference between the dialysate side and the blood side before and after the flow direction of the dialysate is the center in the length direction of the hollow fiber membrane bundle filled in the blood purifier. It is achieved by providing a constriction part in the part, and it is necessary to highly control the assembly state of the membrane and the constriction material for generating the flow resistance of the constriction part. There is a problem that performance fluctuations may occur between blood purifiers or between treatments depending on the state of time (for example, the salt concentration of dialysate).

As a method for solving the above-mentioned problem, for example, by forming a dense skin layer in which no pores are recognized even by observation with an electron microscope at 10,000 times on the inner surface which is a surface in contact with blood of the hollow fiber membrane, A technique for improving the smoothness of the surface, suppressing protein adsorption to the inner surface of the membrane, and suppressing a decrease in β2-microglobulin removal at a high filtration flow rate is disclosed (see Patent Document 27). However, since the hollow fiber type selective separation membrane described in the patent document has a so-called dense uniform structure, the amount of β2-microglobulin that can be removed by the membrane has a limit value called an adsorption saturation amount. . In addition, even though β2-microglobulin could be removed, the removal performance of harmful substances other than β2-microglobulin with a molecular weight of several thousand to several tens of thousands (uremic toxins) is unknown, and such harmful substances are sufficiently removed. I cannot say that.
JP-A-1-94902

  As a method for solving the above-described problems, a therapeutic method for increasing fluid pressure, such as hemodiafiltration, has attracted attention. However, in this method, clogging occurs in the membrane due to blood cell components and proteins in the blood, protein adsorption and protein gel layers are formed on the membrane surface, and a polarized protein layer on the blood side boundary membrane, so-called A secondary layer is formed. Thus, when used for hemodiafiltration and the like, there is a problem that clogging causes solute removal performance to deteriorate over time, and a secondary layer is formed to reduce the filtration flow rate.

As a measure to solve the above problems, a module filled with a hollow fiber type selective separation membrane is flowed bovine blood of hematocrit 25-30% and protein concentration 6-7 g / dl at a flow rate of 200 ml / min, and at a filtration flow rate of 10 ml / min. Hollow fiber type selective separation membrane in which the ratio of β2-microglobulin sieving coefficient when blood filtration is performed at a filtration flow rate of 50 ml / min to the sieving coefficient of β2-microglobulin when blood filtration is 60% or more Is disclosed (see Patent Document 28).
JP 2001-38172 A

The hollow fiber type selective separation membrane disclosed in Patent Document 28 is compatible with the HDFIII-a type (hemodialysis filter small volume replacement type: filtration flow rate 45 ml / min) proposed by the Japanese Dialysis Medical Association as a guideline. The hollow fiber type selective separation membrane to be used is the HDFIII-b type (hemodialysis filter small-volume liquid replacement type: filtration flow rate 90 ml / min) for the purpose of further improving the performance. For example, refer nonpatent literature 1).
Hideki Kawanishi et al., “Dialysis Society Journal 38 (2), P149-154, 2005”

  In Example 4 of Patent Document 28, a hollow fiber membrane having a pressure resistance capable of withstanding a filtration flow rate of 90 ml / min is shown, but no mention is made regarding the separation characteristics at the filtration flow rate of 90 ml / min. According to the study by the present inventors, as the filtration flow rate increases, the blood cell components and proteins in the blood cause clogging of the membrane, or protein adsorption and protein gel layers are formed on the membrane surface, The hollow fiber membrane disclosed in Patent Document 28 is applied to the above HDFIII-b type in order to further increase the problems caused by the formation of a polarized protein layer at the side boundary membrane, that is, a so-called secondary layer. It was difficult.

  The present invention is suitable as an HDFIII-b type blood purifier (hereinafter referred to as HDFIII-b type blood purifier) which is free from the above-mentioned problems in the prior art, that is, presented as a guideline by the Japanese Dialysis Medical Association. In a dry type blood purifier, even when sterilization treatment is performed by radiation irradiation in the absence of a radical scavenger, deterioration of the selectively permeable hollow fiber membrane due to the radiation irradiation is suppressed, and high water permeability is achieved. An object of the present invention is to provide a blood purifier that is excellent in selective separation, has little change in performance over time, and has excellent long-term storage stability.

The present invention relates to a blood purifier filled with a polysulfone-based permselective hollow fiber membrane bundle containing polyvinylpyrrolidone so as to have a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard), and hematocrit (Ht) 40 ±. When bovine blood adjusted to 2.0% and total protein concentration 6.5 ± 0.5 g / dl was flowed at 300 ml / min and filtration rate 90 ml / min, β2- When the screening coefficient of microglobulin is SCβ2MG (15 minutes) and SCβ2MG (120 minutes), respectively, SCβ2MG (120 minutes) / SCβ2MG (15 minutes) ≧ 0.6, and the hollow fiber membrane bundle is arranged in the longitudinal direction. Divided into 10 parts, and when the test defined by the dialysis artificial kidney device manufacturing approval criteria was conducted for each part, the hydrogen peroxide elution amount of the obtained extract was all parts In a polysulfone-based hollow fiber membrane type blood purifier is 5ppm or less.
In this case, the amount of polyvinylpyrrolidone eluted from the hollow fiber membrane bundle is preferably 10 ppm or less.
In this case, the polysulfone-based permselective hollow fiber membrane preferably has a dense layer on the blood contact surface, and the dense layer is preferably composed of an aggregate of aggregated particles having a diameter of 20 to 200 nm.
In this case, the standard deviation value of the particle size distribution of the aggregated particles forming the dense layer is preferably less than 0.5 times the average value.
In this case, the maximum protrusion height (PV value) on the blood contact surface of the hollow fiber membrane is preferably 0.5 μm or less.
In this case, the methylene blue adsorption rate of the hollow fiber membrane is preferably 40% or more and 80% or less.
In this case, a hematocrit (Ht) of 40 ± 2.0% and a total protein concentration of 6.5 ± 0.5 g / dl are adjusted to a blood purifier having a membrane area of 1.5 m ² (based on the hollow fiber membrane inner diameter) It is preferable that the sieving coefficient of bovine serum albumin 15 minutes after starting blood filtration at a filtration rate of 90 ml / min is 0.1 or less.
Also, in this case, after storing the sterilized blood purifier at room temperature for 1 year or longer, the hollow fiber membrane bundle is divided into 10 pieces in the longitudinal direction, and the dialysis-type artificial kidney device manufacturing approval standards for each part When a predetermined test is performed, it is preferable that the UV (220 to 350 nm) absorbance in the extract of the hollow fiber membrane bundle is 0.10 or less at all sites.

  Since the blood purifier of the present invention is of a dry type, it has advantages such as being light, not freezing, and difficult to propagate various germs. In addition, the blood purifier of the present invention has the advantages of having high water permeability in blood purification treatment for removing a large amount of water, excellent selective separation, and little change with time in the performance, HDFIII-b type It has the feature that it can be adapted as a blood purifier. In addition, since the radical scavenger is not included, there is an advantage that when it is used for blood purification, an operation for washing and removing the radical scavenger in advance is unnecessary. Furthermore, in the present invention, even in the dry state and in the absence of a radical scavenger, even if irradiated with radiation, the effect of the conventional technique that the deterioration of the selectively permeable hollow fiber membrane due to irradiation is suppressed is not achieved Therefore, the production of hydrogen peroxide due to the deterioration reaction is small, and the blood purifier of the present invention has the advantage of excellent long-term storage stability. For example, the polysulfone-based permselective hollow fiber membrane loaded in the blood purifier suppresses the generation of hydrogen peroxide even when irradiated with radiation, such as polyvinylpyrrolidone caused by the hydrogen peroxide. Therefore, even if the blood purifier is stored for a long period of time, the maximum value of UV (220-350 nm) absorbance, which is the dialysis-type artificial kidney device manufacturing approval standard, can be maintained at 0.10 or less. There is an advantage that safety can be secured when the purifier is stored for a long period of time.

で示される繰り返し単位をもつポリスルホン樹脂やポリエーテルスルホン樹脂がポリスルホン系樹脂として広く市販されており、入手も容易なため好ましい。 Hereinafter, the present invention will be described in detail.
The hollow fiber membrane bundle used in the present invention is characterized in that it is composed of a polysulfone resin containing polyvinylpyrrolidone. The polysulfone resin in the present invention is a general term for resins having a sulfone bond and is not particularly limited.

A polysulfone resin or a polyethersulfone resin having a repeating unit represented by is widely available as a polysulfone resin and is preferable because it is easily available.

  Polyvinyl pyrrolidone used in the present invention is a water-soluble polymer compound obtained by vinyl polymerization of N-vinyl pyrrolidone, “Kollidon” from BASF, “Prasdon” from ISP, and “Pittscall” from Daiichi Kogyo Seiyaku. Are commercially available under the trade name “,” and there are products of various molecular weights. In general, it is preferable to use a low molecular weight in terms of imparting hydrophilicity, while a high molecular weight is preferable in terms of reducing the amount of elution, but in accordance with the required characteristics of the hollow fiber membrane bundle of the final product. It is selected appropriately. Those having a single molecular weight may be used, or two or more products having different molecular weights may be mixed and used. Moreover, you may use what refine | purified a commercial product and sharpened molecular weight distribution, for example.

  In the present invention, it is preferable to produce a selectively permeable hollow fiber membrane bundle using polyvinylpyrrolidone having a hydrogen peroxide content of 300 ppm or less. By setting the hydrogen peroxide content in the polyvinylpyrrolidone used as a raw material to 300 ppm or less, the hydrogen peroxide elution amount in the hollow fiber membrane bundle after film formation can be easily suppressed to 5 ppm or less. This is preferable because the quality of the hollow fiber membrane bundle can be stabilized. The hydrogen peroxide content in the polyvinylpyrrolidone used as a raw material is more preferably 250 ppm or less, further preferably 200 ppm or less, and further preferably 150 ppm or less.

  The presence of hydrogen peroxide in the polyvinyl pyrrolidone used as a raw material is considered to trigger the oxidative degradation of polyvinyl pyrrolidone, which increases explosively with the progress of oxidative degradation, and further oxidative degradation of polyvinyl pyrrolidone. It is thought that it promotes. Therefore, setting the hydrogen peroxide content to 300 ppm or less is the first means for suppressing the oxidative degradation of polyvinylpyrrolidone in the process of producing a selectively permeable hollow fiber membrane. It is also effective and recommended to take measures to suppress deterioration during transportation and storage of polyvinylpyrrolidone at the raw material stage. For example, it is preferable to use an aluminum foil laminated bag to shield the light and enclose with an inert gas such as nitrogen gas, or enclose and store an oxygen scavenger together. In addition, it is preferable that the measurement and preparation when the package is opened and subdivided be performed after inert gas replacement, and the above-mentioned measures are taken for the storage. Also, in the manufacturing process of the hollow fiber membrane bundle, it is recommended as a preferred embodiment to take a measure such as replacing the inside of the raw material supply tank with an inert gas. Moreover, it is not excluded to use polyvinylpyrrolidone in which the amount of hydrogen peroxide is reduced by a recrystallization method or an extraction method.

  The method for producing the selectively permeable hollow fiber membrane of the present invention is not limited in any way, but for example, a hollow fiber membrane type that can be produced by a method known in Japanese Patent Application Laid-Open No. 2000-300663 is preferable. For example, 16 parts by mass of polyethersulfone (4800P, manufactured by Sumitomo Chemical Co., Ltd.) and 5 parts by mass of polyvinyl pyrrolidone (K-90, manufactured by BASF) disclosed in the patent document, 74 parts by mass of dimethylacetamide, 5 parts by mass of water Was mixed and dissolved, and the defoamed solution was used as a film-forming solution, and a 50% dimethylacetamide aqueous solution was used as a hollow forming agent. This was simultaneously discharged from the outside and inside of the double tube orifice, and passed through a 50 cm free running portion. An example is a method in which a hollow fiber membrane is formed in a coagulation bath composed of water at 75 ° C., formed by rinsing after water washing, and drying at 60 ° C.

  The content of polyvinyl pyrrolidone in the membrane relative to the polysulfone resin in the present invention may be within a range that can impart sufficient hydrophilicity to the hollow fiber membrane, with 99 to 80% by mass of the polysulfone resin and 1 to 20 polyvinyl pyrrolidone. It is preferable that it is mass%. When the content of polyvinyl pyrrolidone is too small with respect to the polysulfone-based resin, the hydrophilicity imparting effect of the film may be insufficient. Therefore, the content is more preferably 1.5% by mass or more, and 2.0% by mass. % Or more is more preferable, and 2.5 mass% or more is further more preferable. On the other hand, if the content is too large, the effect of imparting hydrophilicity is saturated and the amount of polyvinylpyrrolidone and / or oxidatively deteriorated material eluted from the membrane increases, and the amount of polyvinylpyrrolidone eluted from the membrane described later becomes 10 ppm. May exceed. Therefore, it is more preferably 18% by mass or less, further preferably 15% by mass or less, still more preferably 13% by mass or less, and particularly preferably 10% by mass or less.

  Further, in the present invention, the elution of polyvinylpyrrolidone from the polysulfone-based permselective hollow fiber membrane bundle is 10 ppm or less, and the hollow fiber membrane bundle is divided into 10 pieces in the longitudinal direction, and each part is dialyzed. When the test defined by the type artificial kidney device manufacturing approval standard is carried out, it is preferable that the hydrogen peroxide elution amount of the obtained extract is 5 ppm or less at all sites.

  When the elution amount of hydrogen peroxide from the selectively permeable hollow fiber membrane exceeds 5 ppm, the storage stability deteriorates due to the oxidative degradation of polyvinylpyrrolidone by the hydrogen peroxide as described above. In this case, the amount of polyvinylpyrrolidone eluted may increase. In terms of storage stability, the increase in the elution amount of the polyvinyl pyrrolidone is the most prominent phenomenon. In addition, the deterioration of the polysulfone resin is caused and the hollow fiber membrane becomes brittle, or the polyurethane system used for assembling the blood purifier There is a possibility that the deterioration of the adhesive is promoted and the amount of elution of deteriorated substances such as urethane oligomers is increased, leading to a decrease in safety. The increase in the amount of eluate caused by deterioration caused by the oxidizing action of hydrogen peroxide during long-term storage can be evaluated by measuring UV (220-350 nm) absorbance set by the dialysis-type artificial kidney device manufacturing approval standard.

  The elution amount of hydrogen peroxide was also quantified using an extract extracted by a method according to the dissolution test method of the dialysis artificial kidney device manufacturing approval standard.

  As described above, even when hydrogen peroxide is present in a specific part of the hollow fiber membrane bundle, the deterioration reaction of the hollow fiber membrane bundle material starts from that point and propagates throughout the hollow fiber membrane bundle. It is necessary to ensure that the amount of the hollow fiber membrane bundle used in the purifier is in a certain length or less over the entire region. That is, when oxidative degradation of polyvinylpyrrolidone occurs due to hydrogen peroxide present at a specific site, this degradation reaction spreads throughout the entire hollow fiber membrane bundle, and the amount of hydrogen peroxide further increases due to the degradation. Degraded polyvinyl pyrrolidone has a lower molecular weight, and is thus more easily eluted from the hollow fiber membrane bundle. This deterioration reaction proceeds in a chain. Therefore, when the hollow fiber membrane bundle is stored for a long period of time, the elution amount of hydrogen peroxide and polyvinylpyrrolidone increases, which may lead to a decrease in safety when used as a blood purifier. Therefore, it is preferable that the polysulfone-based permselective hollow fiber membrane bundle is divided into 10 pieces in the longitudinal direction and the amount of hydrogen peroxide eluted when measured for each bundle is 5 ppm or less at all sites. 4 ppm or less is more preferable, and 3 ppm or less is more preferable.

  As a method of controlling the elution amount of hydrogen peroxide to the above regulated range, for example, as described above, it is effective to make the amount of hydrogen peroxide in polyvinylpyrrolidone used as a raw material 300 ppm or less, Since the hydrogen peroxide is also generated during the manufacturing process of the hollow fiber membrane bundle, it is necessary to strictly control the manufacturing conditions of the hollow fiber membrane bundle. In particular, optimization of the drying conditions is important because the production of the spinning solution during the production of the hollow fiber membrane bundle greatly contributes to the production in the drying step. In particular, this optimization of the drying conditions is an effective means for reducing the fluctuation in the elution amount in the longitudinal direction of the hollow fiber membrane bundle.

  Regarding the dissolution process of the film-forming solution, for example, when stirring and dissolving a spinning solution composed of a polysulfone resin, polyvinylpyrrolidone, and a solvent, if hydrogen peroxide is contained in the polyvinylpyrrolidone, it exists in the dissolution tank. It was found that hydrogen peroxide increased explosively due to the effects of oxygen and heating during dissolution. Therefore, when charging the raw material into the dissolution tank, it is preferable to input the raw material into the dissolution tank that has been previously replaced with an inert gas. As the inert gas, nitrogen, argon or the like is preferably used. Moreover, although a solvent, and a non-solvent may be added depending on the case, it is also a preferable embodiment that oxygen dissolved in these solvent and non-solvent is replaced with an inert gas.

  In addition, as another method for suppressing the generation of hydrogen peroxide, it is an important requirement to dissolve the film forming solution in a short time. For this purpose, it is usually sufficient to increase the dissolution temperature and / or increase the stirring speed. However, when it does so, degradation and decomposition of polyvinyl pyrrolidone will proceed due to the influence of temperature, stirring linear velocity and shearing force. In fact, according to the study by the inventors, the molecular weight of polyvinylpyrrolidone in the film-forming solution moves in the direction of decomposition (shifts to the low molecular side) as the dissolution temperature increases, or the low molecular side. The appearance of a shoulder that appears to be a decomposition product was observed. From the above, raising the temperature for the purpose of improving the dissolution rate of the raw material accelerates the degradation and degradation of polyvinylpyrrolidone, and consequently blends the degradation product of polyvinylpyrrolidone into the selectively permeable hollow fiber membrane. . For example, when the obtained hollow fiber membrane is used for blood purification, a degradation product is eluted in the blood, and it has not been excellent in terms of product quality safety. Then, it tried to mix a raw material at low temperature in order to suppress decomposition | disassembly of polyvinylpyrrolidone. Even if it is low-temperature dissolution, it is usually preferable to have a temperature of 5 ° C. or higher and 70 ° C. or lower because it requires a running cost under extreme conditions that are below freezing. 60 degrees C or less is more preferable. However, simply lowering the melting temperature causes degradation of polyvinylpyrrolidone due to the longer melting time, lowering the operability and increasing the size of the equipment, which causes problems in industrial implementation. In particular, when polyvinyl pyrrolidone is dissolved at a low temperature, the polyvinyl pyrrolidone becomes a powdered powder, which makes it difficult to dissolve further, or has a problem that it takes a long time for uniform dissolution.

  As a result of examining the dissolution conditions for dissolving at low temperature without taking time, it was found that it is preferable to knead the components constituting the spinning solution prior to dissolution, and the present invention was reached. The kneading may be performed by kneading together the components such as polysulfone resin, polyvinyl pyrrolidone and solvent, or polyvinyl pyrrolidone and polysulfone resin may be kneaded separately. As mentioned above, polyvinylpyrrolidone is accelerated by contact with oxygen and leads to the generation of hydrogen peroxide. Therefore, consideration must be given to suppressing contact with oxygen, such as in an atmosphere substituted with an inert gas, even during kneading. It is preferable to carry out in a separate line. A method of supplying only the polyvinyl pyrrolidone and the solvent and supplying the polysulfone resin directly to the dissolution tank without pre-kneading is also included in the scope of the present invention.

  The kneading may be performed by providing a kneading line separately from the dissolving tank, and the kneaded product may be supplied to the dissolving tank, or both the kneading and dissolving may be performed in a dissolving tank having a kneading function. The type and form of the kneading apparatus in the former separate apparatus are not limited. Either a batch system or a continuous system may be used. A static method such as a static mixer may be used, or a dynamic method such as a kneader or a stirring kneader may be used. The latter is preferable in consideration of kneading efficiency. The kneading method in the latter case is not limited, and any type such as a pin type, a screw type, and a stirrer type may be used. Screw type is preferred. What is necessary is just to select suitably the shape and rotation speed of a screw from the balance of kneading | mixing efficiency and heat_generation | fever. On the other hand, the type of the dissolution tank when using a dissolution tank having a kneading function is not limited. For example, a kneading and dissolving machine having a kneading effect by a so-called planetary motion in which two frame-type blades rotate and revolve. Is recommended. For example, a planetary mixer or a trimix manufactured by Inoue Seisakusho Co., Ltd. corresponds to this method.

  The ratio of the resin component such as polyvinyl pyrrolidone or polysulfone resin and the solvent during kneading is not limited. A resin / solvent mass ratio of 0.1 to 3 is preferred. 0.5-2 are more preferable.

  As described above, the technical point of the present invention is to suppress the degradation of polyvinyl pyrrolidone and perform efficient dissolution. Therefore, it is preferable that the system containing at least polyvinylpyrrolidone is kneaded and dissolved at a low temperature of 70 ° C. or lower in a nitrogen atmosphere. When the polyvinyl pyrrolidone and the polysulfone resin are kneaded in separate lines, this requirement may be applied to the polysulfone resin kneading line. The efficiency of kneading and dissolution and heat generation are two contradictory phenomena. Selection of an apparatus and conditions that avoid the trade-off as much as possible is an important element of the present invention. In this sense, the cooling method in the kneading mechanism is important and needs attention.

Subsequently, the material kneaded by the above method is dissolved. Although the dissolution method is not limited, for example, a dissolution method using a stirring type dissolution apparatus can be applied. In order to dissolve at a low temperature for a short time (within 10 hours), the Froude number (Fr = n ² d / g) is 0.7 to 1.3 and the stirring Reynolds number (Re = nd ² ρ / μ) is It is preferable that they are 50 or more and 250 or less. Where n is the blade rotation speed (rps), ρ is the density (Kg / m ³ ), μ is the viscosity (Pa · s), g is the gravitational acceleration (= 9.8 m / s ² ), and d is the stirring blade diameter. (M). If the Froude number is too large, the inertial force becomes strong, so that the raw material scattered in the tank adheres to the walls and ceiling, and the desired film-forming solution composition may not be obtained. Therefore, the fluid number is more preferably 1.25 or less, further preferably 1.2 or less, and further preferably 1.15 or less. On the other hand, if the fluid number is too small, the inertial force is weakened, so that the dispersibility of the raw material is lowered, and in particular, polyvinylpyrrolidone becomes a spatter, which makes it difficult to dissolve further or requires a long time for uniform dissolution. Sometimes. Therefore, the fluid number is more preferably 0.75 or more, and further preferably 0.8 or more.

  Since the film-forming solution in the present invention is a so-called low-viscosity fluid, if the stirring Reynolds number is too large, a long defoaming time or insufficient defoaming occurs due to entrapment of bubbles in the film-forming solution during stirring. Problems may occur. Therefore, the stirring Reynolds number is more preferably 240 or less, further preferably 230 or less, and still more preferably 220 or less. On the other hand, when the stirring Reynolds number is too small, the stirring force becomes small, so that dissolution may be easily made nonuniform. Therefore, the stirring Reynolds number is more preferably 35 or more, further preferably 40 or more, still more preferably 55 or more, and particularly preferably 60 or more. Furthermore, when a hollow fiber membrane is formed with such a membrane-forming solution, the operability is deteriorated due to a drop in spinnability due to bubbles, and the quality of the material also becomes a defect due to the inclusion of bubbles in the hollow fiber membrane. It turned out to be a problem by causing a decrease in airtightness and burst pressure. Defoaming the film-forming solution is an effective countermeasure, but it may be accompanied by a change in the composition of the film-forming solution due to viscosity control of the film-forming solution or evaporation of the solvent. .

Furthermore, since polyvinyl pyrrolidone tends to undergo oxidative degradation due to the influence of oxygen in the air, it is preferable to dissolve the film forming solution in an inert gas enclosure. Nitrogen, argon, etc. are raised as the inert gas, but nitrogen is preferably used. At this time, the residual oxygen concentration in the dissolution tank is preferably 3% or less. If the nitrogen filling pressure is increased, the melting time can be shortened. However, in order to increase the pressure, the equipment cost is increased, and from the viewpoint of work safety, atmospheric pressure and 2 kgf / cm ² or less are preferable.

  In addition, as the shape of the stirring blade used for dissolving the low-viscosity film forming solution used in the present invention, a radial turbine blade such as a disk turbine type, a paddle type, a curved blade fan turbine type, an arrow blade turbine type, or a propeller type An axial-flow type wing such as an inclined paddle type or a fiddler type is included, but is not limited thereto.

  By using the low-temperature dissolution method as described above, it is possible to obtain a highly safe hollow fiber membrane in which the degradation degradation of polyvinylpyrrolidone is suppressed. In addition, it is preferable to use a film-forming solution having a residence time after dissolution of the raw materials within 24 hours for film-forming. This is because thermal energy was accumulated while the film forming solution was kept warm, and a tendency to cause deterioration of the raw material was recognized.

  As a method for controlling the elution amount of hydrogen peroxide within the above regulated range, it is important to reduce contact with oxygen even in the drying step. For example, drying in an atmosphere substituted with an inert gas can be mentioned, but it is disadvantageous in terms of economy. As an economical drying method, a method of drying by irradiating microwaves under reduced pressure is effective and recommended. In performing so-called drying by removing a liquid from an object to be dried, it is well known that each of them is irradiated with reduced pressure and microwave. However, performing decompression and irradiating microwaves at the same time is a combination that is generally difficult to use in combination with microwave characteristics. The inventors of the present application adopt a combination with this difficulty in order to achieve improvement in safety and productivity by preventing oxidative degradation of polyvinylpyrrolidone and reducing the amount of eluate from the hollow fiber membrane, and drying conditions. It was found that the problem can be solved by a method that is economically advantageous by optimizing the above.

  As drying conditions of the drying method, it is preferable to irradiate microwaves with an output of 0.1 to 100 kW under a reduced pressure of 20 kPa or less. Moreover, it is preferable that the frequency of this microwave is 1,000-5,000 MHz, and the highest ultimate temperature of the hollow fiber membrane bundle during a drying process is 90 degrees C or less. If a means of decompression is also provided, drying of moisture will be promoted by itself, so there is an advantage that the microwave irradiation output can be reduced and the irradiation time can be shortened, but the temperature rise can also be made relatively low. Overall, there is little influence on the performance degradation of the hollow fiber membrane bundle. Furthermore, drying accompanied by means of reduced pressure has the advantage that the drying temperature can be relatively lowered, and in particular, there is a significant point that degradation degradation of polyvinylpyrrolidone can be remarkably suppressed. An appropriate drying temperature is sufficient from 20 to 80 ° C. More preferably, it is 20-60 degreeC, More preferably, it is 20-50 degreeC, More preferably, it is 30-45 degreeC.

  The accompanying decompression means that the decompression is uniformly applied to the center part and the outer peripheral part of the hollow fiber membrane bundle, the evaporation of moisture is promoted uniformly, and the hollow fiber membrane is uniformly dried. Therefore, the failure of the hollow fiber membrane bundle due to non-uniform drying is corrected. In addition, heating by microwaves also acts almost equally on the entire center and outer periphery of the hollow fiber membrane bundle, so it functions synergistically in uniform heating, and is unique in drying the hollow fiber membrane bundle. It will be of significance. The degree of vacuum may be set as appropriate depending on the output of the microwave, the total moisture content of the hollow fiber membrane bundle and the number of hollow fiber membrane bundles, but in order to prevent temperature rise of the hollow fiber membrane bundle during drying, the degree of vacuum is It is performed at 20 kPa or less, more preferably 15 kPa or less, and further preferably 10 kPa or less. If it exceeds 20 kPa, not only will the water evaporation efficiency decrease, but the temperature of the polymer constituting the hollow fiber membrane bundle may rise and deteriorate. Moreover, although the one where a pressure reduction degree is higher is preferable in the meaning which raises temperature rise suppression and drying efficiency, since the cost concerning maintaining the sealing degree of an apparatus becomes high, 0.1 kPa or more is preferable. More preferably, it is 0.25 kPa or more, and further preferably 0.4 kPa or more.

In consideration of shortening the drying time, a higher microwave output is preferable.For example, in hollow fiber membrane bundles containing polyvinylpyrrolidone, degradation or decomposition of polyvinylpyrrolidone occurs due to overdrying or overheating, or wettability during use. It is preferable not to increase the output much because there is a problem such as a decrease. Further, the hollow fiber membrane bundle can be dried even with an output of less than 0.1 kW, but there is a possibility that a problem of reduction in throughput due to an increase in drying time may occur. The optimum value of the combination of the degree of decompression and the microwave output varies depending on the water content of the hollow fiber membrane bundle and the number of processed hollow fiber membrane bundles, and it is preferable to obtain a set value as appropriate through trial and error.
For example, as a temporary guide for carrying out the drying conditions of the present invention, when 20 hollow fiber membrane bundles having a moisture content of 50 g per hollow fiber membrane bundle are dried, the total moisture content is 50 g × 20 fibers = 1,000 g. At this time, it is appropriate that the microwave output is 1.5 kW and the decompression degree is 5 kPa.

  A more preferable microwave output is 0.1 to 80 kW, and a more preferable microwave output is 0.1 to 60 kW. The output of the microwave is determined by, for example, the total number of hollow fiber membrane bundles and the total water content, but when the microwave is suddenly irradiated, drying is completed in a short time, but the hollow fiber membrane is partially denatured. May cause deformation such as curling. When drying using microwaves, for example, when using something like a water retention agent in the hollow fiber membrane, high power and extreme drying using microwaves will disappear due to scattering of the water retention agent It becomes the cause of. In particular, when accompanied by conditions of reduced pressure, considering the influence on the hollow fiber membrane, conventionally, it was not intended to irradiate microwaves under reduced pressure. Irradiation of microwaves under reduced pressure of the present invention means that the evaporation of aqueous liquid becomes active in a relatively low temperature state, so that degradation of polyvinylpyrrolidone due to high output microwave and high temperature, deformation of hollow fiber membrane, etc. This has a double effect of preventing damage to the hollow fiber membrane.

  Although the present invention enables one-stage drying in which the microwave output is constant, i.e., drying by microwaves under reduced pressure, as another embodiment, the microwave output is sequentially changed according to the progress of drying. So-called multi-stage drying, which lowers in stages, is included as a preferred embodiment. Therefore, the significance of multi-stage drying will be described as follows. When drying with microwaves at a relatively low temperature of about 30 to 90 ° C. under reduced pressure, multi-stage drying in which the output of the microwaves is sequentially reduced in accordance with the progress of drying of the hollow fiber membrane bundle. The method is excellent. The degree of pressure reduction, temperature, microwave output, and irradiation time may be determined in consideration of the total amount of hollow fiber membranes to be dried, appropriate industrially acceptable drying time, and the like. Multistage drying can be performed in any number of stages, for example, 2 to 6 stages, but it is appropriate to use 2 to 3 stages of drying that is industrially appropriate in consideration of productivity. Depending on the total amount of water contained in the hollow fiber membrane bundle, when relatively large, multistage drying is performed at a temperature of 90 ° C. or lower, for example, at a reduced pressure of about 5 to 20 kPa, and the first stage is 30 to 100 kW. The range can be determined in consideration of the microwave irradiation time such that the second stage is in the range of 10 to 30 kW and the third stage is in the range of 0.1 to 10 kW. When the output difference of the microwave is large, for example, 90 kW at the high stage and 0.1 kW at the low stage, the number of stages to reduce the output may be increased to 4 to 8 stages, for example. In the case of the present invention, since technical consideration is given to the microwave irradiation called decompression, there is an advantage that the microwave output can be relatively lowered. For example, the first stage is about 10 to 100 minutes by 10 to 20 kW microwave, the second stage is about 3 to 10 kW and about 5 to 80 minutes, and the third stage is about 0.1 to 3 kW and about 1 to 60 minutes. Dry in stages. It is preferable that the microwave output and irradiation time of each stage are lowered in conjunction with the reduction in the total amount of moisture contained in the hollow fiber membrane. This drying method is a very gentle drying method for hollow fiber membrane bundles, and cannot be expected in the prior art, thus making the effects of the present invention significant.

  To explain another aspect, when the moisture content of the hollow fiber membrane bundle is 400% by mass or less, irradiation with a low-power microwave of 12 kW or less may be excellent. For example, when the amount of water in the total amount of the hollow fiber membrane bundle is about 1 to 7 kg, the output is 12 kW or less under a reduced pressure of about 3 to 10 kPa at a temperature of 80 ° C. or less, preferably 60 ° C. or less. For example, about 1 to 5 kW of microwave for 10 to 240 minutes, less than 0.5 to 1 kW of microwave for about 1 to 240 minutes, more preferably about 3 to 240 minutes, less than 0.1 to 0.5 kW Drying is performed uniformly by adjusting the irradiation power and irradiation time of the microphone mouth wave according to the degree of drying. The degree of vacuum is set to 0.1 to 20 kPa for each stage, but the first stage having a relatively high moisture content of the hollow fiber membrane is increased to 0.1 to 5 kPa, for example, and the microwave output is increased. The degree of pressure reduction at each stage, in which the microwave is irradiated at a pressure slightly higher than the first stage of 0.1 to 5 kW under a reduced pressure of 5 to 20 kPa in the second stage and the third stage. It is possible to arbitrarily set the appropriate adjustment in accordance with the change in consideration of the transition of the total moisture content and the moisture content of the hollow fiber membrane bundle. In each stage, the operation of changing the degree of reduced pressure further increases the significance of irradiating microwaves under reduced pressure according to the present invention. Of course, it is necessary to always consider the uniform irradiation and exhaust of the microwave in the microwave irradiation apparatus.

  The drying of the hollow fiber membrane bundle is performed by irradiating with microwaves under reduced pressure, and using a drying method that alternately reverses the direction of ventilation also makes the process complicated in drying, but an effective drying method It is. The microwave irradiation method and the alternating ventilation reverse method also have merits and demerits, and these can be used in combination when high quality is required. In the first stage, when the ventilation alternating reversal method is adopted and the average moisture content proceeds to about 20 to 60% by mass, it can be dried by irradiating microwaves under reduced pressure in the next stage. In this case, after drying by irradiating microwaves, a ventilation drying method in which the ventilation direction is alternately reversed can be used in combination. These can be determined in consideration of the quality of the hollow fiber membrane produced by drying, in particular, the quality of the polysulfone-based permselective hollow fiber membrane bundle having no partial fixation in the length direction of the hollow fiber membrane. These drying methods can be performed simultaneously, but are not practical because of disadvantages such as the complexity and complexity of the apparatus and the price increase. However, the combined use of an effective heating method such as far infrared rays is not excluded from the scope of the drying method of the present invention.

  The maximum temperature reached by the hollow fiber membrane bundle during drying can be measured by applying an irreversible thermolabel to the side of the film that protects the hollow fiber membrane bundle, drying, and checking the display after taking out the drying. . At this time, the maximum reached temperature of the hollow fiber membrane bundle during drying is preferably 90 ° C. or lower, more preferably 80 ° C. or lower. More preferably, it is 70 degrees C or less. If the maximum temperature reached exceeds 90 ° C., the film structure is likely to change, which may cause performance degradation or oxidative degradation. In particular, in a hollow fiber membrane bundle containing polyvinylpyrrolidone, it is necessary to prevent the temperature rise as much as possible because polyvinylpyrrolidone is easily decomposed by heat. Temperature rise can be prevented by optimizing the degree of decompression and microwave output and irradiating intermittently. Moreover, although the one where a drying temperature is lower is preferable, 30 degreeC or more is preferable from the surface of the maintenance cost of pressure reduction degree, and the shortening of drying time.

The microwave irradiation frequency is preferably 1,000 to 5,000 MHz in consideration of the suppression of irradiation spots on the hollow fiber membrane bundle and the effect of extruding water in the pores from the pores. More preferably, it is 1,500-4,000 MHz, More preferably, it is 2,000-3,000 MHz.
In drying by microwave irradiation, it is important to uniformly heat and dry the hollow fiber membrane bundle. In the above-described microwave drying, nonuniform heating due to the reflected wave that occurs accompanying the generation of the microwave occurs, so it is important to take measures to reduce the nonuniform heating due to the reflected wave. The method is not limited and is arbitrary. For example, a method of providing a reflector in an oven disclosed in Japanese Patent Application Laid-Open No. 2000-340356 to reflect reflected waves and uniformize heating is a preferred embodiment. One.

  After the water content of the hollow fiber membrane bundle is reduced to 10 to 20% by mass, the hollow fiber membrane bundle is preferably dried by irradiation with far infrared rays. Although it is preferable to irradiate microwaves or to perform drying by heating (ventilation) in the sense that the material to be dried is dried more quickly, in the case of a separation membrane containing polyvinylpyrrolidone, polyvinylpyrrolidone progresses in drying, that is, in the hollow fiber membrane. As the moisture content decreases, there is a problem that it is susceptible to degradation and degradation by heat. Therefore, in the final stage of drying (low water content), it is a preferred embodiment to dry mildly with lower energy. Further, far-infrared rays are a kind of electromagnetic wave and are preferable because they penetrate into the material to be dried as in the case of microwaves.

  The irradiation wavelength of far infrared rays is preferably 1 to 30 μm. Since water and organic matter have a high absorption rate of far infrared rays having a wavelength of 3 to 12 μm, it is difficult to raise the temperature of the object to be dried even if the wavelength of the far infrared rays is too short or too long. Such costs may increase. Therefore, the wavelength of the far infrared ray to be irradiated is more preferably 1.5 to 26 μm, further preferably 2 to 22 μm, and further preferably 2.5 to 18 μm.

As a radiation medium for irradiating far infrared rays, a stainless steel medium having a metal oxide film on its surface is preferably used. For example, it is inexpensive to use a far-infrared radiator in which austenitic stainless steel powder is coated with an oxide metal such as Al ₂ O ₃ , Fe ₂ O ₃ , TiO ₂ , CaO, MgO, K ₂ O, and Na ₂ O. This is a more preferable embodiment because far infrared rays can be extracted efficiently.

  On the other hand, in the case of drying by far-infrared irradiation performed after the completion of microwave drying, unlike the case of microwave drying, the discharge phenomenon does not occur even if irradiation is performed under reduced pressure. It can be carried out. From the point of drying efficiency, 5 kPa or less is preferable, 4 kPa or less is more preferable, 3 kPa or less is more preferable, and 2 kPa or less is more preferable. The irradiation energy of the far-infrared irradiation is preferably controlled so as to be 80 ° C. or lower at a temperature detected by a thermocouple provided at the center of the oven. It is more preferable to control at 70 ° C. or lower. This far-infrared radiation is highly absorbed by water and converted to energy, has excellent thermal efficiency, and has the safety that temperature control according to the transition of drying can be made appropriate. Have advantages. This is significant in terms of dry finishing in order to maintain the surface effects including the drying method by far-infrared irradiation, the color of the hollow fiber membrane bundle, the surface roughness, bending, cracking, smoothness and soft feeling.

A specific embodiment of a preferable drying method in the present invention includes: (1) a drying step of simultaneously irradiating the hollow fiber membrane bundle with microwave irradiation and far-infrared irradiation; (2) a drying step of performing microwave irradiation; It includes embodiments of a plurality of drying processes called drying processes that perform infrared irradiation. The proper drying method of the present invention employs a drying process in which (A) a hollow fiber membrane bundle is simultaneously subjected to (1) microwave irradiation and far-infrared irradiation, and the moisture content of the hollow fiber membrane bundle is lowered to a constant value. In general, a drying method that employs a drying step of (3) far-infrared irradiation is common. Another aspect of the drying method is that (B) a hollow fiber membrane bundle adopts (2) a drying step in which microwave irradiation is performed, and the moisture content of the hollow fiber membrane bundle is lowered to a constant value, (3) It is a drying method that employs a drying process that performs far-infrared irradiation. Of course, it is an essential requirement for each drying step to adopt appropriate temperature control, pressure control when performing under reduced pressure, and ventilation exhaust when necessary.
Theoretically, (1) Drying step and (2) Drying step are used together, (3) Drying step and (1) Drying step are used together, (2) Drying step and (3) Drying step are used together Although it is on-site operation of the drying apparatus for carrying out the drying method of the present invention, and the like, it is feasible, but compared to the drying methods of (A) and (B), the practical result is I have not examined it enough.

  As described above, the far-infrared irradiation may be started after the microwave irradiation is completed, or may be performed at the time of the microwave irradiation, and the microwave drying and the far-infrared drying may be performed simultaneously. By performing microwave and far-infrared irradiation simultaneously, evaporation of water that has been excited by microwave irradiation and moved to the surface of the hollow fiber membrane is accelerated by irradiation with far-infrared radiation, leading to improved drying efficiency. Further, this efficient evaporation of surface moisture suppresses the concentration fluctuation of the surface of the hollow fiber membrane of polyvinylpyrrolidone induced by the surface moisture, which is preferable because it leads to suppression of partial sticking. As described above, microwave drying is preferably performed under reduced pressure. Therefore, microwave drying and far-infrared drying are simultaneously performed under reduced pressure, and microwave irradiation is performed when the moisture content is reached. A method of stopping, continuing the far-infrared irradiation while maintaining the reduced pressure state, and continuing further drying is preferable. At this time, after the microwave irradiation is completed, the degree of decompression of the system may be lowered and conditioning may be performed, and then the degree of decompression may be increased again to start far-infrared irradiation. Therefore, in the present invention, it is preferable to perform drying using a microwave dryer in which a far-infrared heater is attached in the heating oven and an exhaust system capable of reducing the pressure in the heating oven is attached. It is an aspect.

  When drying under conditions of reduced pressure and temperature by microwave drying and far-infrared drying, generally, for example, when high-power microwaves are applied in a short time under reduced pressure and high temperature, the moisture content decreases. However, since the uneven distribution of moisture and polyvinyl pyrrolidone are also related to microwave heating, it induces a phenomenon such as bumping, which damages the material and porous structure of the hollow fiber membrane bundle, and bursts. There is a risk that a structure that can cope with pressure cannot be guaranteed. The present invention appropriately adjusts the output of microwaves and far-infrared rays, and also adjusts the environment of temperature and pressure, thereby promoting the overall drying of the inside and outside of the hollow fiber membrane bundle by microwaves in particular. Thus, the drying of the whole including the surface of the hollow fiber membrane bundle by the far infrared ray is promoted, and the microwave drying and the far infrared drying increase the synergistic drying effect.

  In the present invention, it is a preferred embodiment to use an inert gas such as nitrogen gas when the inside of the drying chamber is returned to normal pressure after the drying is completed. Immediately after the drying, the temperature of the hollow fiber membrane bundle is high, so when returning the inside of the drying chamber to atmospheric pressure, when a gas containing oxygen such as air is fed, in the case of a hollow fiber membrane containing polyvinylpyrrolidone, polyvinylpyrrolidone May undergo oxidative degradation due to the effects of oxygen and heat. Therefore, when the inside of the drying chamber is returned to normal pressure after the drying is completed, the oxidative deterioration of the polyvinyl pyrrolidone in the hollow fiber membrane bundle is suppressed by feeding the inert gas.

  For the drying of the hollow fiber membrane bundle, the use of microwaves and far-infrared rays for an unlimited time does not affect the quality. This is because the influence of thermal deterioration of the polysulfone resin constituting the hollow fiber membrane bundle or of the polyvinylpyrrolidone material and environmental deterioration such as oxygen, water, and steam can be considered. Therefore, in view of industrial production, it is necessary to consider an appropriate time that is naturally allowed for the drying time. From the viewpoint of protecting the quality of the hollow fiber membrane subjected to relatively harsh drying conditions such as microwaves and far infrared rays, from the viewpoint of industrial productivity, the inventors of the present invention are from the start to the end of drying. The drying time is preferably within 3 hours. More preferably within 2.5 hours, still more preferably within 2 hours.

Furthermore, it is preferable that the hollow fiber membrane does not dry out. When it is completely dried, the detailed reason is unknown, but the deterioration of polyvinyl pyrrolidone increases, and the production of hydrogen peroxide may be greatly increased. In addition, wettability may be reduced during re-wetting during use, and polyvinyl pyrrolidone may be difficult to absorb water, and thus may be easily eluted from the hollow fiber membrane. The moisture content of the hollow fiber membrane after drying is preferably 1% by mass or more and less than the saturated moisture content. 1.5 mass% or more is more preferable. If the water content of the hollow fiber membrane is too high, bacteria may proliferate during storage, the hollow fiber membrane may crush due to its own weight, or adhesive failure may occur during assembly of the blood purifier. Therefore, the moisture content of the hollow fiber membrane is preferably 10% by mass or less, more preferably 7% by mass or less. In addition, the moisture content as used in the field of this invention measures the mass (g) of a hollow fiber membrane bundle, and after that, vacuum-drying is performed for 12 hours under reduced pressure (-750 mmHg or less), and the mass (g) after drying is measured. To do. The difference between before and after drying is determined as a weight loss (g) in% based on the mass (g) after drying. The water content is determined by the following formula.
(Weight loss / mass after drying) × 100 = moisture content (mass%)

  In addition, as described above, a method of removing hydrogen peroxide mixed from the raw material polyvinylpyrrolidone or generated in the manufacturing process of the hollow fiber membrane bundle by washing is also effective as a method for controlling the above-described characteristic values within a regulated range. is there.

  In the present invention, the amount of polyvinylpyrrolidone to be described later and endotoxin, which is an endotoxin, are prevented from entering the blood side, and the hollow fiber membrane bundles are prevented from sticking together when the hollow fiber membrane bundles are dried. In order to balance the properties, the content of polyvinyl pyrrolidone in the outermost surface layer of the hollow fiber membrane bundle is preferably in a specific range. As a method for satisfying this requirement, it can be achieved, for example, by setting the content of polyvinylpyrrolidone with respect to the polysulfone resin to the above-mentioned range, or optimizing the film forming conditions of the hollow fiber membrane bundle. It is also an effective method to wash the formed hollow fiber membrane bundle. As film forming conditions, it is effective to adjust the humidity of the air gap part at the nozzle outlet, stretching conditions, the temperature of the coagulation liquid, the composition ratio of the solvent and non-solvent in the coagulation liquid, and the introduction of a cleaning process is effective. It is.

In the present invention, as described above, in the process of producing a hollow fiber membrane bundle, as a means for reducing the elution amount of hydrogen peroxide or bringing the content of polyvinylpyrrolidone on the outer surface of the hollow fiber membrane bundle into a specific range. It is important to introduce a washing step before the drying step. For example, the hollow fiber membrane bundle that has passed through the water-washing bath is wound into a basket in a wet state to form a bundle of 3,000 to 20,000. Next, the obtained hollow fiber membrane bundle is washed to remove excess solvent, polyvinylpyrrolidone. As a method for washing the hollow fiber membrane bundle, in the present invention, it is preferable to treat the hollow fiber membrane bundle by immersing it in hot water at 70 to 130 ° C. or room temperature to 50 ° C. and 10 to 40 vol% ethanol or isopropanol aqueous solution. .
(1) In the case of hot water washing, the hollow fiber membrane bundle is immersed in excess RO water and treated at 70 to 90 ° C. for 15 to 60 minutes, and then the hollow fiber membrane bundle is taken out and subjected to centrifugal dehydration. This operation is repeated several times while updating the RO water to perform the cleaning process.
(2) A method of treating a hollow fiber membrane bundle immersed in excess RO water in a pressurized container at 121 ° C. for about 2 hours may be employed.
(3) When using an ethanol or isopropanol aqueous solution, it is preferable to repeat the same operation as in (1).
(4) It is also a preferable washing method that the hollow fiber membrane bundle is radially arranged in the centrifugal washer, and centrifugal washing is performed for 30 minutes to 5 hours while spraying washing water at 40 ° C. to 90 ° C. from the rotation center in a shower shape. .
Two or more cleaning methods may be combined. In any method, when the processing temperature is too low, it is necessary to increase the number of times of cleaning, which may lead to an increase in cost. On the other hand, if the treatment temperature is too high, the decomposition of polyvinylpyrrolidone is accelerated, and conversely, the cleaning efficiency may be reduced. By performing the above-described cleaning, it is possible to optimize the content of polyvinyl pyrrolidone on the outermost surface layer, to suppress sticking and to reduce the amount of eluate, and also to reduce the hydrogen peroxide elution amount.

  The polysulfone-based permselective hollow fiber membrane bundle obtained by the above method is stored for 3 months or more in a dry state, and then subjected to the test defined by the dialysis artificial kidney device manufacturing approval criteria and the hollow fiber membrane extract. It is preferable that the maximum value of UV (220 to 350 nm) absorbance at 0.10 is 0.10 or less. In the evaluation, the dried sample was stored in a dry box (atmosphere: air) conditioned at a humidity of 50% RH for 3 months at room temperature, and then UV (220-350 nm) absorbance was measured by the method described above. . In consideration of storing the hollow fiber membrane bundle in a dry state in the manufacturing process of the hollow fiber membrane bundle, transportation, stock storage, and the like, it is preferable to impart the above characteristics.

In the present invention, a hematocrit (Ht) 40 is placed in a blood purifier filled with a polysulfone-based permselective hollow fiber membrane bundle having the above properties so as to have a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard). When bovine blood adjusted to ± 2.0% and total protein concentration 6.5 ± 0.5 g / dl was flowed at 300 ml / min at a filtration rate of 90 ml / min, β2 at 15 minutes and 120 minutes after the start of blood filtration. -It is preferable that SCβ2MG (120 minutes) / SCβ2MG (15 minutes) ≧ 0.6 when the screening coefficient of microglobulin is SCβ2MG (15 minutes) and SCβ2MG (120 minutes), respectively. 0.65 or more is more preferable, and 0.7 or more is more preferable. If SCβ2MG (120 minutes) / SCβ2MG (15 minutes) is less than 0.6, the membrane may become clogged and the removal amount of β2 microglobulin may be insufficient, and the therapeutic effect may not be sufficiently obtained. is there.

  In order to effectively demonstrate the effects of the present invention, it is preferable that the β2-microglobulin removal ability itself is high. In particular, in the present invention, it is preferable that sufficient performance is maintained even 120 minutes after the start of filtration. Therefore, SCβ2MG (120 minutes) ≧ 0.5 is preferable. More preferably, it is 0.6 or more.

Further, although it is desirable to improve the removal performance of β2-microglobulin, the effectiveness in blood purification treatment is diminished if leakage of albumin, which is a useful protein, increases. Therefore, it is necessary to use a membrane that sufficiently suppresses leakage of albumin. The sieving coefficient of the albumin is preferably 0.1 or less. Generally, since the leakage amount of albumin decreases with time, the sieving coefficient is set to a value after 15 minutes, which is the initial stage of the filtering operation. That is, to a blood purifier with a membrane area of 1.5 m ² (inside of hollow fiber membrane inner diameter), bovine blood adjusted to hematocrit (Ht) 40 ± 2.0% and total protein concentration 6.5 ± 0.5 g / dl. In addition to the above characteristics, it is satisfied that the sieving coefficient (SCalb (15 minutes)) of bovine serum albumin 15 minutes after the start of blood filtration is 0.1 or less at a filtration rate of 90 ml / min at a flow rate of 300 ml / min. preferable. It is more preferable that SCalb (15 minutes) ≦ 0.07, and SCalb (15 minutes) ≦ 0.05 is more preferable.

  By satisfying the above characteristics, it is possible to impart selective separability between useful proteins and unnecessary proteins and stability over time. Moreover, the compatibility as a HDFIII-b type blood purifier is acquired by providing the said characteristic.

  Although the method to provide the said characteristic is not limited, The following method is mentioned as a preferable embodiment.

  The permselective hollow fiber membrane of the present invention preferably has a dense layer on the inner surface of the hollow fiber membrane on the blood contact surface side, and the dense layer is preferably composed of an aggregate of aggregated particles. In the membrane having such a structure, the size of the aggregated particles constituting the dense layer is largely related to the selective permeability for fractionating the solute to be permeated or the solute not to be permeated. For example, when used for blood purification, the Stokes diameter of a low molecular protein to be permeated is approximately 5 nm or less, and therefore the pore size of the membrane is suitably several nm. Specifically, the Stokes diameter of β2-microglobulin to be removed is about 3 nm, and albumin to be retained is about 8 nm. In blood purification, fractionation between these two proteins is necessary, and the pore diameter formed by the particle gaps in the dense layer preferably has a size for fractionation. The gap formed by the 20-200 nm particles, which is the average particle size of the preferred aggregated particles in the present invention, has a size of around several nm and forms an optimum pore size for fractionation of the low molecular protein region. . The average particle diameter of the aggregated particles is more preferably 40 to 150 nm, and still more preferably 60 to 120 nm. Further, when the standard deviation of the particle size distribution of the aggregated particles is large, voids formed from the particles become very nonuniform. An excessively large void is not preferable because albumin permeation occurs at the beginning of filtration. Further, as the filtration proceeds, the membrane (pores) is clogged due to albumin entering the voids, and the change with time (decrease) in performance increases. In this case, the passage of time also affects the permeation performance of substances that can permeate sufficiently, such as β2-microglobulin. Conversely, if the gap is too small, the solute to be transmitted cannot be transmitted.

  From these factors, the particle size distribution of the aggregated particles is preferably 0.5 times or less of the average value as the standard deviation. More preferably, it is 0.3 times or less, More preferably, it is 0.2 times or less. In particular, in the blood purification treatment with a large amount of filtration, which is an object of the present invention, an improvement effect for these problems is more exhibited. When the standard deviation exceeds 0.5 times the average value, a large number of particles having a distance between the centers of the particles constituting the dense layer that are at least twice the particle diameter are present. In the case of such a structure, it becomes easy to randomly form a packed structure in which small particle groups enter the voids formed by large particles, and an optimal uniform pore size distribution cannot be formed. In such a distribution state, when a high pressure is applied and a filtration operation to obtain a large filtration flow rate is performed, the liquid flow concentrates on the large pore diameter portion, and the formation of the protein gel layer and consolidation of the gel layer over time. Is accelerated, and blockage of the large pore diameter portion, which is originally responsible for the permeation of low molecular weight proteins, is likely to occur. According to the Hagen-Poiseuille rule, when the hole diameter is doubled, the flow rate flowing there is 16 times. That is, a plasma protein load of 16 times is imposed on the pores. The particle size distribution of the agglomerated particles described in the present invention has an effect as a standard deviation having an effect of relaxing the function of the pores responsible for the specific and efficient low molecular protein permeation. The characteristic is 0.5 times or less of the value, more preferably 0.3 times or less, and further preferably 0.2 times or less.

  The formation of aggregated particles in the dense layer is considered to be performed by the following process. When the spinning solution is brought into contact with a coagulation liquid or a hollow forming agent, a decrease in the solvent concentration and an increase in the non-solvent concentration occur rapidly at the interface between the film forming solution and the coagulation liquid. At this time, the polymer that has been uniformly dissolved increases the interaction between the polymers, so that a large number of polymer-rich phases are formed in the vicinity of the interface, which becomes the core of the particle. Thereafter, the polymer rapidly precipitates around the nucleus to grow particles. The grown particles come into contact with each other, and an aggregated structure of particles is formed. In the process of forming the agglomerated structure, mainly, (1) formation of particle nuclei (influence on the number of particles), (2) particle growth (influence on particle size), (3) aggregation of particles ( It can be divided into the process of forming boundary surfaces as individual particles, that is, affecting the gap between particles. The method for increasing the particle size of the aggregated particles and the uniformity of the particle size is not limited, but it is preferable to control the step (2), which greatly affects the size of the particles and the uniformity thereof. .

  For example, the following methods can be exemplified. First, when the polymer concentration in the film-forming solution is high (about 40% by mass or more), the formation of particles is performed in a polymer-rich system, so the formation of the boundary surface of the particles is not sufficient, and the particle structure is not a clear particle structure. May be a complicated structure. On the other hand, when the concentration is low (about 12% by mass or less), the degree of entanglement between the polymers in the initial stage is low, so that nucleation and particle growth are significantly reduced, and the formation of a dense layer is substantially reduced. It does not occur, or the dense layer is not a structure in which particles are aggregated but a network structure. Therefore, optimization of the polymer concentration is important. That is, the polymer concentration is preferably 15 to 35% by mass as the total of the polysulfone resin and polyvinylpyrrolidone in the film forming solution. More preferably, it is 17-30 mass%. Furthermore, in order to reduce the standard deviation of the particle size distribution of the aggregated particles, optimization by a combination of the following requirements is preferable. In the dense layer, the formation of the polymer rich portion and the polymer poor portion proceeds rapidly in the process of nucleation to growth. Here, polymer diffusion is the dominant process. Factors for film formation that affect diffusivity are related to the viscosity and temperature of the film formation solution. Specifically, the higher the temperature (lower the viscosity), the greater the diffusibility of the polymer, and the particle growth proceeds. The gap tends to increase. The solution temperature in this case is the temperature (nozzle temperature) when the film forming solution is discharged from the spinneret (nozzle). However, as the nozzle temperature is raised, the standard deviation of the particle distribution tends to increase, so optimization is necessary. 30-80 degreeC is preferable and, as for the temperature (nozzle temperature) at the time of discharging a film forming solution, 40-60 degreeC is more preferable. In addition, increasing the solvent concentration of the hollow forming agent of the hollow fiber membrane also greatly contributes to increasing the particle size and reducing the standard deviation of the particle size distribution. It is presumed that the solidification of the polymer particles between the film-forming solution and the hollow forming agent becomes slow (accelerates phase separation), so that the particle growth tends to increase.

  Furthermore, as a result of intensive studies by the inventors of the present application, in the die (double tube orifice type), the cross-sectional area of the central hole for discharging the hollow forming agent and the cross-sectional area of the hollow portion of the hollow fiber membrane to be formed are specified. We have found that it is preferable to make it a region. When the hollow fiber membrane is produced with the aim of having a perfect circular inner diameter of 200 μm, the desired hollow fiber membrane can be obtained by setting the center hole diameter of the die to around 100 μm and the draft ratio to 2 or less. From the examination of the die having various center holes, the ratio is preferably such that the center hole diameter of the hollow forming agent is 0.7 or less with respect to the inner diameter of the hollow fiber membrane. Although this mechanism is not clear, when the amount of hollow forming agent required to obtain the target hollow fiber membrane inner diameter is discharged, the hollow forming agent side becomes positive pressure and expands the discharged membrane forming solution. Happens. At this time, the hollow forming agent quickly penetrates into the dense layer formed on the inner surface, causing the temperature of the dense layer and the concentration gradient of the coagulating liquid to be uniform, and uniforming the particle size distribution of the aggregated particles. It is assumed that it contributes to The ratio of the center hole diameter of the die to the inner diameter of the hollow fiber membrane is preferably small, but a very small one is not preferred from the viewpoint of the processing accuracy of the die and the washability of the die. The center hole diameter is preferably 60 μm or more. Therefore, the ratio of the center hole diameter of the die to the inner diameter of the hollow fiber is preferably 0.3 to 0.7.

  There is another problem to be solved in the present invention. Controlling the size and particle size distribution of aggregated particles that form a dense layer that acts as a separation active layer for membrane permeation as described above, even when suppressing changes in the removal performance of low molecular weight proteins due to clogging of the membrane during blood purification treatment However, in order to suppress a decrease over time due to hemodialysis, it is preferable to smooth the surface roughness of the inner surface, which is the blood contact surface of the hollow fiber membrane.

  That is, the maximum protrusion height (PV value) on the inner surface side of the hollow fiber membrane is preferably 0.5 μm or less. 0.4 μm or less is more preferable, and 0.3 μm or less is more preferable. The lower limit is not limited, but in order to ensure smoothness in industrial production, there is a limit, and about 0.01 μm is preferable. When the maximum protrusion height (PV value) exceeds 0.5 μm, blood protrusions and proteins in the blood are stimulated by the protrusions, and protein adsorption and protein gel layers are formed on the membrane surface. A polarized protein layer, a so-called secondary layer is formed, and clogging occurs in hemodiafiltration, so that the solute removal performance decreases with time, and the secondary layer is formed, resulting in a decrease in filtration flow rate. There is.

  The PV value represents the difference between the maximum value and the minimum value of the unevenness of all measurement points with respect to the reference point when the unevenness of the film surface is measured. Also, the smoothness of these film surfaces can be obtained from an analysis device such as a three-dimensional surface structure analysis microscope using a scanning white interference method, and can be calculated from measured values. A known device can be used as the measurement device. For example, an interference image is collected on a test piece while scanning the interference objective lens in the optical axis direction by a scanning white interference microscope, and the information on the digitized interference intensity is used as a work piece. The target PV value can be obtained by processing at the station.

  The smoothness of the surface on the inner surface side of the hollow fiber membrane described above is affected by the content of the polyvinyl pyrrolidone on the inner surface and the coagulation rate in the hollow fiber membrane formation process. In order to satisfy other characteristics, it is preferable to form a film under the conditions described later.

  In order to satisfy the stability over time due to hemodialysis, it is preferable to simultaneously optimize the negative charge on the inner surface of the hollow fiber membrane in addition to satisfying the smoothness of the surface. The negatively charged state of the inner surface of the hollow fiber membrane can be evaluated by the adsorption rate of methylene blue.

  The methylene blue adsorption rate of the hollow fiber membrane is preferably 40% or more and 80% or less. Methylene blue is a cationic compound and has the property of binding when contacted with an anionic substance. It is also conceivable that methylene blue is physically adsorbed on the film surface. Therefore, the methylene blue adsorption rate referred to here can be considered as an indicator of the charge state of the inner surface of the membrane, the hydrophilic-hydrophobic balance, and the nonspecific adsorption ability. When the adsorption rate of methylene blue is in the range of 40% or more and 80% or less, it is considered that an appropriate charge state is obtained, the membrane surface state is optimized, and the blood compatibility is excellent. When the adsorption rate of methylene blue is less than 40%, the negative charge becomes too small, the electrostatic interaction with the negatively charged platelets becomes strong, and the platelets tend to adhere and blood compatibility is lowered. Sometimes. Accordingly, the methylene blue adsorption rate is more preferably 42% or more, and further preferably 45% or more. When the adsorption rate is 80% or more, the negative charge becomes too strong, the hydrophobic interaction and non-specific adsorption increase, blood components are easily adsorbed, and the durability of the blood purification function may be inferior. Furthermore, if the negative charge is strong, kinin production in the blood is induced, which may result in poor blood compatibility. Therefore, the methylene blue adsorption rate is more preferably 78% or less, and further preferably 75% or less.

The methylene blue adsorption rate in the present invention is a value calculated from the methylene blue concentration in the solution before and after perfusion of the methylene blue solution by the following method.
(1) A methylene blue solution is prepared by dissolving methylene blue in water to a concentration of 0.5 ppm.
(2) Sampling the methylene blue solution before contact with the membrane.
(3) Measure 1000 mL of methylene blue solution and fill the blood side and dialysate side of the blood purifier with a membrane area of 1.5 m ² .
(4) After filling the blood purifier, pool the excess methylene blue solution and perfuse the blood side of the blood purifier at a flow rate of 200 mL / min. At this time, a circuit is constructed so that the solution flowing out of the solution pool passes through the blood side of the blood purifier and returns to the pool.
(5) After perfusion for 5 minutes, the methylene blue solution filled in the blood purifier and the pooled methylene blue solution are combined and sampled.
(6) A calibration curve is created from the absorbance at the maximum absorption wavelength of 490 nm in the ultraviolet absorption spectrum of the methylene blue aqueous solution, and the concentration of the methylene blue solution before and after contact with the membrane is measured.
(7) The methylene blue adsorption rate is calculated from the following equation.
(Methylene blue adsorption rate) [%] = 100 × (methylene blue concentration of solution after perfusion) / (methylene blue concentration of solution before perfusion)

  In the present invention, the content of polyvinyl pyrrolidone on the innermost outermost layer is preferably 20 to 45% by mass. 25-40 mass% is more preferable, and 28-37 mass% is further more preferable. If the content of polyvinyl pyrrolidone on the innermost surface layer is less than 20% by mass, the content of polyvinyl pyrrolidone in the entire membrane becomes too low, and blood compatibility and permeation performance may be deteriorated. In the case of a dry film, the priming property may be deteriorated. Conversely, if it exceeds 45 mass%, elution of polyvinylpyrrolidone from the membrane may not be suppressed, and if such a membrane is used for blood purification therapy, it may lead to a cause of xenobiotic reactions (such as blood clots). There is sex. In addition, endotoxin (endotoxin) contained in the dialysate is more likely to enter the blood side, which may lead to side effects such as fever.

  In the present invention, as a means for imparting the above-mentioned characteristics including blood compatibility, the balance of polyvinylpyrrolidone and polysulfone resin is controlled on the inner surface which is the blood contact surface of the hollow fiber membrane. To have a negative charge and to smooth the surface.

  The balance between hydrophilicity and hydrophobicity depends on the ratio of polyvinylpyrrolidone and polysulfone resin in the spinning dope, the heat history during dissolution of the spinning dope, the crosslinked state of polyvinylpyrrolidone during irradiation, and the air gap length in the spinning process. Further, it is preferable to control by solidification conditions (composition, concentration, temperature) and drying conditions. In order to have an appropriate negative charge, in the spinning process, when the membrane forming solution is discharged from the outside of the double spinneret and the hollow forming agent is discharged from the inside of the double spinneret, there is a gap between the hollow forming agent and the film forming solution. In addition, it is preferable that static electricity is moderately suppressed in the running process and winding process of the hollow fiber membrane during the spinning process.

  The methylene blue adsorption rate is also an important factor due to the degradation reaction of polyvinylpyrrolidone present in the outermost layer on the inner surface of the hollow fiber membrane. The deterioration reaction of the surface polyvinyl pyrrolidone proceeds at an accelerated rate when it is overdried in the drying process of the hollow fiber membrane. For example, when the hollow fiber membrane is overdried in a state where the surface polyvinylpyrrolidone content is high, the degradation reaction of polyvinylpyrrolidone proceeds. When the surface polyvinylpyrrolidone is high, the hydrophilicity should be high and the adsorption of methylene blue should be suppressed, and the blood compatibility should be good. However, when the surface polyvinylpyrrolidone deteriorates, the adsorption rate of methylene blue increases, We have empirically found that the compatibility is reduced. The reason is not clear, but it is presumed that the adsorption rate of methylene blue is increased by opening the pyrrolidone ring in polyvinylpyrrolidone to form a carboxyl group and changing the negative charge balance on the inner surface.

  In the hollow fiber membrane for a blood purifier, the characteristics on the outer surface side as well as the characteristics on the inner surface side are important.

  In this invention, it is preferable that content in the outermost surface layer of the hollow fiber membrane of the above-mentioned polyvinyl pyrrolidone is 25-50 mass%. If the content of polyvinyl pyrrolidone on the outermost surface layer is less than 25% by mass, the content of polyvinyl pyrrolidone on the entire membrane, particularly on the inner surface of the membrane becomes too low, and blood compatibility and permeation performance may be deteriorated. In the case of a dry film, the priming property may be lowered. When the hemodialyzer is used for blood purification therapy, it is necessary to perform wetting and defoaming by allowing physiological saline or the like to flow inside and outside the hollow fiber membrane of the hemodialyzer. In this priming operation, the roundness of the hollow fiber membrane, edge crushing, deformation, hydrophilicity of the membrane material, etc. are thought to affect the priming properties, but the hollow fiber membrane comprising a polysulfone resin and polyvinylpyrrolidone In the case of a dry membrane blood purifier, the hydrophilic / hydrophobic balance of the hollow fiber membrane greatly affects the priming property. Therefore, the content of polyvinylpyrrolidone in the outermost outermost layer is more preferably 27% by mass or more, further preferably 29% by mass or more, and further more preferably 31% by mass or more. In addition, if the content of polyvinyl pyrrolidone on the outermost surface layer exceeds 50% by mass, the endotoxin (endotoxin) contained in the dialysate is likely to enter the blood side, leading to side effects such as fever. When the membrane is dried, polyvinyl pyrrolidone present on the outer surface of the membrane intervenes and the hollow fiber membranes stick to each other (adhere), which may cause problems such as deterioration in workability of the blood purifier assembly. Therefore, 47 mass% or less is more preferable, 43 mass% or less is further more preferable, and 41 mass% or less is further more preferable.

  As a method for bringing the content and pore diameter of polyvinylpyrrolidone in the innermost surface layer and outermost surface layer of the hollow fiber membrane described above into the above-mentioned ranges, for example, the composition ratio of polyvinylpyrrolidone to the polysulfone resin in the membrane-forming solution is 65:35 to 90:10, or by optimizing the film forming conditions of the hollow fiber membrane. It is also an effective method to wash the formed hollow fiber membrane. As film forming conditions, humidity adjustment of the air gap part at the nozzle outlet, stretching conditions, temperature of the coagulation bath, optimization of the composition ratio of the solvent and the non-solvent in the coagulation liquid, etc. Washing, alcohol washing, centrifugal washing and the like are effective. Among these methods, as the film forming conditions, optimization of the humidity of the air gap and the composition ratio of the solvent and the non-solvent in the external coagulating liquid is particularly effective as the cleaning method.

  The air gap portion is preferably surrounded by a member for blocking outside air, and the humidity inside the air gap is preferably adjusted by the composition of the spinning dope, the nozzle temperature, the air gap length, the temperature of the external coagulation bath, and the composition. For example, a spinning stock solution composed of polyethersulfone / polyvinylpyrrolidone / dimethylacetamide / RO water = 10-25 / 0.5 to 12.5 / 52.5 to 89.5 / 0 to 10.0 at 30 to 60 ° C. When discharging from a nozzle, passing through an air gap of 50 to 1000 mm, and leading to an external coagulation bath having a concentration of 0 to 70 mass% and a temperature of 50 to 80 ° C., the absolute humidity of the air gap portion is 0.01 to 0.3 kg / kg dry air. By adjusting the humidity of the air gap portion to such a range, it is possible to control the outer surface open area ratio, the outer surface average pore area, and the outer surface polyvinylpyrrolidone content to an appropriate range.

  The air gap length is more preferably 100 to 900 mm, further preferably 200 to 800 mm. If the air gap length is too long, fusion due to yarn breakage and yarn swinging tends to occur, and spinning stability may be lowered. On the other hand, if the air gap length is too short, the progress of phase separation becomes insufficient, and a uniform pore diameter may not be obtained.

When spinning the hollow fiber membrane, the membrane-forming solution is discharged from the double tube type nozzle together with the hollow forming agent, and is guided to the coagulation bath through the idle portion to be solidified. When the hollow forming agent discharge linear velocity immediately after being discharged from the nozzle and the film forming solution discharge linear velocity are in the relationship of hollow forming agent discharge linear velocity> film forming solution discharge linear velocity, the inner surface of the hollow fiber membrane and the hollow forming agent It is preferable because shear stress works at the interface, friction is generated, and appropriate charge is imparted. The hollow forming agent discharge linear velocity is more preferably 3.0 to 10.0 times the film forming solution discharge linear velocity. If it is less than 3.0 times, the stress at the interface between the inner surface of the hollow fiber membrane and the hollow forming agent is small, and there is a possibility that the charge cannot be controlled appropriately. Therefore, 3.5 times or more is more preferable, and 4.0 times or more is more preferable. On the other hand, if it exceeds 10.0 times, the pressure loss of the spinneret becomes large and uneven discharge may occur, resulting in non-uniform film shape. Therefore, 9.5 times or less is more preferable, and 9.0 times or less is further more preferable.
The film forming solution discharge speed is preferably 6000 cm / min or less. If the film-forming solution discharge linear velocity is too high, pressure loss at the spinneret becomes large, and discharge unevenness occurs, spinning may become unstable, and the surface smoothness of the inner surface may decrease.
The discharge linear velocity and the linear velocity ratio can be calculated by the following equation.
(Discharge linear velocity immediately after discharge) (cm / min) = (Discharge amount) (ml / min) / (Discharge hole area) (cm ² )
(Linear velocity ratio) = (Linear velocity of hollow forming agent) / (Linear velocity of film forming solution)

  As a hollow formation agent, 0-80 mass% dimethylacetamide (DMAc) aqueous solution is preferable. More preferably, it is 20-70 mass%, More preferably, it is 25-60 mass%, More preferably, it is 35-50 mass%. By controlling the hollow forming agent concentration within this range, as described above, the particle diameter of the aggregated particles forming the dense layer and the particle diameter distribution can be within a preferable range. Moreover, although the detailed reason is not known, the use of a mixed solution of dimethylacetamide and water causes a change in the mobility of the polysulfone resin and polyvinylpyrrolidone, and the hydrophilicity / hydrophobicity of the blood contact side surface of the hollow fiber membrane after film formation The ratio is thought to be reasonably balanced. If the hollow forming agent concentration is too low, the dense layer on the blood contact surface becomes thick, which may reduce the solute permeability. If the hollow forming agent concentration is too high, the formation of a dense layer is likely to be incomplete, and polyvinylpyrrolidone and endotoxin (fragment) contained in the membrane are likely to elute to the blood side, resulting in decreased biocompatibility (blood) compatibility. Sometimes.

  As the external coagulation liquid, it is preferable to use an NMP or DMAc aqueous solution of 10 to 80 ° C. and 0 to 40% by mass. If the temperature and concentration of the external coagulation solution are too high, the dialysis solution side surface (outer surface) pore ratio and the dialysis solution side surface (outer surface) average pore area will be too large, and blood of endotoxin (fragment) when using dialysis The reverse inflow to the side may increase. If the temperature and concentration of the external coagulation liquid are too low, it is necessary to use a large amount of water to dilute the solvent brought in from the spinning stock solution, and the cost for waste liquid treatment increases. Therefore, the temperature and concentration of the external coagulation liquid are more preferably 20 to 80 ° C. and 0 to 35% by mass, further preferably 30 to 80 ° C. and 0 to 30% by mass, and still more preferably 40 to 80 ° C. and 5 to 30%. It is 50 mass%, Most preferably, it is 50-80 degreeC and 10-30 mass%.

  In the production of the hollow fiber membrane of the present invention, it is preferable that stretching is not substantially applied after the hollow fiber membrane structure is completely fixed. “Substantially no stretching” means that the hollow fiber membrane drawn from the external coagulation liquid is run with only a tension that does not cause slack in the hollow fiber membrane that runs in the subsequent process, and is finally wound on a bag. Means that. If a hollow fiber membrane with a completely fixed membrane structure is stretched, pore deformation, crushing, tearing, and orientation may occur, increasing the elution of polyvinylpyrrolidone and making it easier for endotoxin to leach into the blood side. is there. Due to friction with the contact member and liquid resistance during the film forming process, elongation occurs in the hollow fiber film during travel, and it is difficult to form a film with all the roller speeds being constant. The tension that does not cause slackness specifically means that the roller speed during the spinning process is controlled so that slack or excessive tension does not occur in the spinning dope discharged from the nozzle. The drawing ratio here is the speed ratio between the rollers. A preferable range of the stretch ratio between the rollers is 0.01 to 1.5%. A more preferable range is 0.05 to 1%, and a further preferable range is 0.1 to 0.7%. The discharge linear velocity / coagulation bath first roller velocity ratio (draft ratio) is preferably in the range of 0.95 to 1.8. When the ratio is less than 0.95, the smoothness of the inner surface of the hollow fiber membrane may be lowered. Therefore, the draft ratio is more preferably 0.98 or more, and further preferably 1.0 or more. When the draft ratio exceeds 1.8, the membrane structure may be destroyed, for example, the dense layer of the hollow fiber membrane is torn. Therefore, the draft ratio is more preferably 1.7 or less, still more preferably 1.6 or less, still more preferably 1.5 or less, and particularly preferably 1.4 or less. By adjusting the draft ratio to this range, deformation and destruction of the pores can be prevented, clogging of blood protein into the membrane pores can be prevented, and performance stability over time and sharp fractionation characteristics can be expressed. Is possible.

  Further, it is preferable to optimize the hydrophilicity / hydrophobicity balance of the hollow fiber membrane in the washing step after adjusting the hydrophilicity / hydrophobicity balance to some extent in the spinning step. Furthermore, it is preferable to fix the polyvinylpyrrolidone in the hollow fiber membrane by optimizing the drying conditions. In the washing step, excess polyvinyl pyrrolidone that could not be fixed in the coagulation step is washed away, and localization of the polyvinyl pyrrolidone existing on the film surface and swelling are promoted. On the other hand, in the drying step, the physical interaction between the polysulfone resin and polyvinyl pyrrolidone, that is, the degree of entanglement between the polysulfone resin chain and the polyvinyl pyrrolidone chain can be strengthened, and the hydrophilicity / hydrophobicity balance can be adjusted. As a washing method, it is preferable that the hollow fiber membrane pulled up from the coagulation bath is guided to a water washing tank made of RO water and passed at 30 ° C. or more over 60 seconds or more. The RO water to be used is one obtained by purifying tap water with an RO device, preferably having a specific resistance of 0.3 to 2 MΩcm, more preferably 0.4 to 1.9 MΩcm. 0.5 to 1.7 MΩcm is more preferable, and 0.7 to 1.5 MΩcm is even more preferable. If the temperature is too low, excess polyvinylpyrrolidone cannot be washed out, which may lead to an increase in cost, for example, it is necessary to lengthen the washing tank or slow down the spinning speed. If the temperature is too high, water may boil and the hollow fiber membrane may not run stably, and polyvinylpyrrolidone may be deteriorated by heat. Therefore, the temperature of the washing tank is preferably 90 ° C. or lower. A more preferable temperature is 35 to 80 ° C, more preferably 35 to 75 ° C, and still more preferably 35 to 60 ° C.

  In order to have an appropriate negative charge, it is preferable to reduce static electricity on the film surface. Static electricity on the film surface is generated mainly by drying and friction. Examples of the method for preventing the hollow fiber membrane from drying include not drying completely in the drying step and glycerin treatment. 10-70 mass% is preferable and, as for the density | concentration of the glycerol aqueous solution used for glycerol treatment, 15-65 mass% is more preferable. As another means, it is effective to neutralize the air during drying. The neutralization treatment is performed by neutralizing the static electricity of the membrane by using a static elimination device that generates plus and minus and giving ions of the opposite polarity to the electrode resistance of the hollow fiber membrane according to the charge amount of the membrane. . As a method of supplying ions of opposite polarity according to the amount of charge, the hollow fiber membrane can be directly neutralized using a method using a static eliminator incorporating the Ion Current Control method. The Ion Current Control method senses the charged state of a charged object by sensing the ionic current caused by the potential difference between the charged object and the ground electrode of the static eliminator, and supplies ions of the opposite polarity according to the amount of charge. Thus, the time (pulse width) for applying a high voltage to the positive and negative electrode needles is controlled. As a method of preventing friction that causes static electricity, it is also effective to optimize the materials of the rollers and guides of the spinning machine. Examples of materials for the rollers and guides include Teflon (registered trademark), bakelite, stainless steel, and plastic. Stainless steel that minimizes friction with the hollow fiber membrane is suitable. Moreover, in order to minimize friction with the hollow fiber membrane, it is preferable that the contact portion has a smooth curve. It is also preferable to attach a ground. By controlling the process so that static electricity and friction do not occur in this way, the negative charge inherent in the polysulfone resin can be appropriately controlled.

  The shape of the blood purifier in the present invention is not limited, but a shape in which a selectively permeable hollow fiber membrane bundle is loaded in a blood purifier container and both ends thereof are fixed with a resin is preferable. An example of a blood purifier is shown in FIG.

  The blood purifier 1 is loaded with a selectively permeable hollow fiber membrane bundle 3 in a cylindrical housing 2, and both ends of the hollow fiber membrane bundle 3 are fixed 4 to both ends of the housing 2 with an adhesive or the like. The both ends of 2 are covered with caps 5a and 5b. A dialysate inlet 6a for introducing dialysate into the housing 2 is provided near one end of the side of the housing 2, and a dialysate outlet 6b for discharging dialysate is provided near the other end. Each is formed to protrude. One cap 5a is formed with a blood introduction port 7a for introducing blood into the housing 2, and the other cap 5b is formed with a blood discharge port 7b for discharging blood.

  Then, as shown by an arrow A, blood enters the space formed by the cap 5a and one end face of the selectively permeable hollow fiber membrane bundle 3 from the blood introduction port 7a, and the selectively permeable hollow fiber membrane bundle 3 It passes through the hollow fiber, enters the space formed by the other end face of the selectively permeable hollow fiber bundle 3 and the cap 5b, and is discharged from the blood outlet 7b as shown by an arrow B. On the other hand, the dialysate enters the housing 2 from the dialysate inlet 6a as shown by the arrow C, flows outside the hollow fibers of the selectively permeable hollow fiber membrane bundle 3, and as shown by the arrow D, the dialysate It is discharged from the discharge port 6b. At this time, the flow of blood to be dialyzed and the flow of dialysate are opposite so-called opposite flows. During this time, waste in the blood flowing in the selectively permeable hollow fiber membrane is dialyzed into the outer dialysate through the hollow fiber membrane.

  Examples of the material for the housing and the cap include polycarbonate, polyester, and polypropylene. Examples of the adhesive material used for fixing both ends include polyurethane resin, epoxy resin, and silicone resin.

  The method of injecting the adhesive used for fixing both ends into the fixing portion is not limited, but a centrifugal bonding method in which the injection is performed using the centrifugal force generated by rotating the blood purifier to be injected is recommended. The method of the centrifugal bonding method is not limited. For example, sealing jigs are attached to both ends of the housing loaded with the dried selectively permeable hollow fiber membrane bundle and set in a centrifugal bonding machine. A predetermined amount of uncured adhesive resin is injected from the dialysate inlets 6a and 6b at a temperature near room temperature while rotating the centrifugal adhesive machine at a predetermined rotational speed, and then the temperature of the centrifugal adhesive machine is injected. The curing temperature is raised and the curing is terminated, or at least the resin is precured until the fluidity of the resin is lost, and the centrifugal bonding machine is stopped. In the latter case, heating is performed in a stationary state, post-curing is performed, and curing is terminated. This centrifugal bonding method may be a two-layer centrifugal bonding method in which the selectively permeable hollow fiber membrane at the bonding interface is reinforced by covering the inside of the bonded portion of the selectively permeable hollow fiber membrane bundle with a flexible resin layer.

In the case of the centrifugal bonding method, it is important that the adhesive is uniformly injected into the entire space in the selectively permeable hollow fiber membrane bundle. If this injection becomes non-uniform and a part where the injection amount of the adhesive is insufficient is produced, it leads to poor adhesion. In particular, if there is a portion where the selectively permeable hollow fiber membranes are fixed, penetration of the adhesive is inhibited. Therefore, in order to unravel the adhering portion, for example, so-called yarn setting treatment is performed in which air is blown from the nozzle to the end face of the selectively permeable hollow fiber membrane bundle. Certainly, the present warping treatment is effective in unraveling the fixed hollow fiber membrane, but this treatment is not preferable because it causes deformation of the selectively permeable hollow fiber membrane bundle at the end face portion, leading to the generation of an inclined hollow fiber membrane.
The selectively permeable hollow fiber membrane bundle of the present invention is characterized in that uniformity of the injection of the adhesive is ensured without performing the yarn setting treatment because partial fixation during drying is suppressed. Therefore, the yarn setting process is unnecessary. However, since it is important to ensure the uniformity of the injection of the adhesive, it is preferable to implement the following measures. For example, it is preferable to select a low viscosity brand as the adhesive. The viscosity after 2 minutes of mixing the two liquids is preferably 2000 mPa · s or less. 1600 mPa · s or less is more preferable. Moreover, it is preferable to lower the filling density of the selectively permeable hollow fiber membrane bundle restrained by the hollow package when the dry selectively permeable hollow fiber membrane bundle is inserted into the housing used for assembling the blood purifier.

  The number of hollow fiber membranes and the length of the hollow fiber membrane bundle to be filled are appropriately set according to market requirements and hollow fiber membrane bundle characteristics. The length and diameter of the housing are set so as to match the size of the selectively permeable hollow fiber membrane bundle to be filled.

  The selectively permeable hollow fiber membrane for blood purifiers must be sterilized. As a sterilization method, a radiation sterilization method of irradiating γ rays or electron beams is preferable because of its reliability and simplicity. However, polyvinyl pyrrolidone is deteriorated by irradiation, hydrogen peroxide is generated, and generation thereof is accelerated by hydrogen peroxide present at the time of irradiation. Therefore, it is preferable to have the above-described characteristics even after the irradiation. In order to impart the characteristics even after the radiation irradiation treatment, it is important to use a polysulfone-based permselective hollow fiber membrane having the above characteristics before irradiation, but it is only one of the necessary requirements. . After satisfying this requirement, it is necessary to take measures to suppress the deterioration reaction caused by irradiation.

  Conventionally, in order to satisfy these characteristics, it has been achieved by irradiation with radiation in a wet state and in the presence of a radical scavenger, but it has the above-mentioned problems and has been desired to be improved. An object of the present invention is to solve the above problems and provide a dry type blood purifier and a method capable of suppressing the degradation reaction of polyvinylpyrrolidone due to radiation even when irradiated with radiation in the absence of a radical scavenger. Yes.

  Accordingly, in the present invention, the water content in the polysulfone-based permselective hollow fiber membrane bundle is preferably 600% by mass or less. Moreover, it is preferable that a radical scavenger is not included in the blood purifier during radiation irradiation.

  When the water content exceeds 600% by mass, the weight of the blood purifier increases, so that handling is reduced, transportation costs increase, bacteria are easily generated, freezing in a cold region, and other problems occur. There are things to do. Moreover, since polyvinylpyrrolidone is too cross-linked, the blood coagulation reaction may be activated when used for blood purification. On the other hand, when the water content is less than 0.8% by mass, deterioration of polyvinyl pyrrolidone by irradiation is promoted, and it is determined by increased production of hydrogen peroxide, carboxyl groups, peroxides, etc. May cause an increase in UV (220 to 350 nm) absorbance in a hollow fiber membrane extract, a decrease in long-term storage stability, blood compatibility and stability, and the like. Therefore, 1.0-300 mass% is more preferable, and 1.5-200 mass% is further more preferable.

  In order to impart the above characteristics by irradiation with radiation in the dry state and in the absence of a radical scavenger, the polysulfone-based permselective hollow fiber membrane before irradiation is used as described above, as described above. It is important but only one of the requirements. After satisfying this requirement, it is necessary to take measures to suppress the deterioration reaction caused by irradiation.

  It is difficult to suppress the deterioration reaction due to irradiation in the dry state and in the absence of a radical scavenger, which is the object of the present invention, and conventionally, this is unavoidably performed by a wet method and in the presence of a radical scavenger. It was. As a result of intensive studies on solving the problem, the present inventors have promoted the deterioration reaction by oxygen gas adsorbed on the localized portion of the polyvinyl pyrrolidone of the polysulfone-based permselective hollow fiber membrane, and The present invention was completed by finding a method for suppressing the degradation reaction of polyvinylpyrrolidone based on the presumed mechanism of being suppressed by water adsorbed on the localized portion. Although it is a well-known phenomenon that the deterioration reaction is affected by oxygen, the present inventors have found for the first time that the deterioration reaction is suppressed by a trace amount of water adsorbed on the localized portion of polyvinylpyrrolidone. Phenomenon. Preferred embodiments are described below.

  The present inventors adjusted the moisture content of the hollow fiber membrane to 5% by mass or more using degassed water when irradiating the selectively permeable hollow fiber membrane having the above-described properties in a dry state. It has been found that the blood purifier can suppress the degradation reaction of polyvinylpyrrolidone even in the absence of a radical scavenger.

  That is, all the blood and dialysate entrances and exits of a blood purifier filled with a polysulfone-based permselective hollow fiber membrane bundle containing polyvinylpyrrolidone adjusted to a moisture content of 5 to 600% by mass using deaerated water It is preferable to irradiate with radiation by sealing with a packaging bag that blocks outside air and water vapor in a sealed state.

  In the present invention, the deaerated water present in and around the polysulfone-based permselective hollow fiber membrane is preferably deoxygenated water. Further, it is more preferably inert gas saturated water.

  The deoxygenated water is water having a dissolved oxygen content of 0.5 ppm or less. The dissolved oxygen content is more preferably 0.2 ppm or less, and further preferably 0.1 ppm or less.

Usually, about 20 l of air per 1 m ³ is dissolved in water, and oxygen gas of 8 mg / l water is dissolved in normal tap water. The method for preparing the deoxygenated water is not limited as long as the amount of dissolved oxygen is satisfied. Those prepared by a generally known degassing method can be applied. Examples thereof include a heat degassing method, a vacuum degassing method, a nitrogen gas bubbling method, a membrane degassing method, a reducing agent addition method, and a reducing method. The membrane deaeration method is particularly preferable because the amount of dissolved oxygen can be reduced to the ppb level. The membrane degassing method may be prepared by either a non-porous membrane method or a porous membrane method.

  It is preferable to use the deoxygenated water that has been subjected to reverse osmosis treatment (RO treatment).

  The dissolved oxygen concentration is measured with a dissolved oxygen concentration meter. The dissolved oxygen concentration in water can be measured using, for example, a dissolved oxygen meter OM-51-L1 manufactured by HORIBA Ltd.

  If only deoxygenated water is used, oxygen contained in the surrounding air is dissolved again, and the re-dissolved oxygen gas is adsorbed on the localized portion of polyvinylpyrrolidone, which is preferable as described above. It is difficult to completely suppress the deterioration reaction. This problem can be solved by using an inert gas saturated water such as nitrogen. That is, by containing an inert gas in a saturated state, even when irradiation is performed in an environment where oxygen is included in the surroundings, dissolution of oxygen gas in water is suppressed, and there is a state where the concentration of oxygen contained in water is low. Will be kept.

  The method for preparing the inert gas saturated water is not particularly limited, and a method of bubbling an inert gas such as nitrogen can be suitably used. As known in the art, the inert gas bubbling method is known as a method for removing dissolved oxygen from water, but dissolved oxygen is eventually removed by introduction of inert gas. It is also preferable to dissolve the active gas. Specifically, oxygen is removed by bubbling an inert gas in water from which oxygen has been removed in advance by a heat degassing method, a vacuum degassing method, a membrane degassing method, a reducing agent addition method, or the like, and the inert gas is dissolved. Is done efficiently. Here, the dissolved oxygen amount of the inert gas saturated water is preferably 0.5 ppm or less, more preferably 0.2 ppm or less, and further preferably 0.1 ppm or less. The water used here is preferably RO-treated water.

  By using the degassed water, the degradation of the hollow fiber membrane due to radiation irradiation, particularly the degradation reaction of polyvinylpyrrolidone, is more efficiently suppressed than when non-degassed water is used. Increase in UV (220-350 nm) absorbance in the extract of hollow fiber membranes when the test specified by the approval standard for dialysis-type artificial kidney device manufacturing is increased, anti-thrombogenicity, long-term The effect of suppressing undesirable deterioration reactions that cause a decrease in storage stability and performance development during priming is increased.

  In the present invention, the oxygen concentration in the blood purifier is preferably 3.0% by volume or less. 1.0% by volume or less is more preferable, and 0.1% by volume or less is more preferable. When the oxygen concentration exceeds 3.0% by volume, the hollow fiber membrane, particularly polyvinyl pyrrolidone, may be deteriorated when irradiated with radiation or an electron beam even if the above requirements are satisfied. The expression of the effect of the present invention is further stabilized by adjusting the oxygen concentration.

  In the above method, the mechanism by which the degradation reaction of polyvinylpyrrolidone during irradiation is suppressed is presumed as follows. The polyvinyl pyrrolidone in the hollow fiber membrane is localized in the hollow fiber membrane without being uniformly dispersed, and the water present inside and on the surface of the hollow fiber membrane is selectively around the highly hydrophilic polyvinyl pyrrolidone. It is presumed that it is localized by being adsorbed on the surface. It is presumed that the presence of water around the polyvinyl pyrrolidone blocks the attack of oxygen activated by radiation irradiation on the polyvinyl pyrrolidone and suppresses the degradation reaction. Therefore, it is guessed that the effect is expressed more effectively by deaeration water conversion. In addition, in the present invention, a hollow fiber membrane is used in which the amount of hydrogen peroxide that is activated by radiation and causes a deterioration reaction is suppressed in the same manner as oxygen, so that the deterioration reaction is also suppressed. It is presumed that the effect of the present invention is manifested by heavy effects.

  The method for reducing the oxygen concentration in the blood purifier is not limited, but it is preferable to fill the blood purifier with an inert gas. As described above, the blood purifier is assembled using the hollow fiber membrane bundle dried by the above-described method, deoxygenated water is injected and filled into the blood purifier, and the air present in the blood purifier is expelled. A method of simultaneously performing deoxygenation and oxygen concentration reduction by injecting and filling an inert gas into the module after filling the moisture in the hollow fiber membrane and the periphery of the hollow fiber membrane with deoxygenated water is preferable. The inert gas is preferably nitrogen gas from the viewpoint of economy.

  In the above method, it is preferable to seal all the blood and dialysate inlet / outlet of the blood purifier after adjusting the water content and oxygen concentration in the blood purifier. By this method, the volatilization of moisture from the hollow fiber membrane filled in the blood purifier is suppressed, and the invasion of oxygen gas contained in the outside air into the blood purifier is suppressed, so that the effect of the present invention is achieved. Is effectively expressed. In addition, invasion of various germs into the blood purifier can be prevented. Moreover, since the volatilization of moisture from the hollow fiber membrane is suppressed for a long period of time, shrinkage due to the hollow fiber membrane being dried over time and deterioration of the membrane characteristics are suppressed. Therefore, the effect that the generation | occurrence | production of a defect, the fall of a film | membrane characteristic, etc. at the time of storing a blood purifier for a long term is suppressed appears. For example, when the shrinkage of the hollow fiber membrane occurs, peeling of the interface between the hollow fiber membrane and the adhesive at the fixing portion to the blood purifier due to the adhesive of the hollow fiber membrane occurs, leading to the occurrence of liquid leakage at the portion. Further, in the case of a method in which crimping is applied to the hollow fiber membrane to suppress the dialysis fluid drift, the crimping of the dialysis fluid may increase due to the relaxation of the crimp due to the drying of the hollow fiber membrane.

  In the present invention, it is preferable that the blood purifier hermetically sealed by the above method is sealed with the aforementioned packaging bag and irradiated with radiation. By sealing with the packaging bag, contamination of the outer surface of the blood purifier, adhesion of germs and the like are prevented. In the method, the atmospheric gas in the packaging bag is not particularly limited. Air may be used, but an inert gas atmosphere such as nitrogen gas is more preferable because it suppresses the growth of various bacteria (aerobic bacteria) mixed after sterilization and the effect of the above-mentioned sealing plug is complemented. Furthermore, in the present invention, it is preferable to irradiate with radiation and electron beams after sealing tightly as will be described later. Therefore, there is an advantage that oxygen gas can be prevented from entering the blood purifier from outside air during this period. is there. As an inert gas atmosphere, it is preferable to seal the oxygen scavenger together with the blood purifier.

  The oxygen scavenger is not limited as long as it has a oxygen scavenging function. For example, sulfite, bisulfite, dithionite, hydroquinone, catechol, resorcin, pyrogallol, gallic acid, longalit, ascorbic acid and / or its salts, sorbose, glucose, lignin, dibutylhydroxytoluene, dibutylhydroxyanisole, Examples of the oxygen scavenger include a ferrous salt, metal powder such as iron powder, and the like, which can be selected as appropriate. In addition, oxygen scavengers for metal powders are used as an oxidation catalyst, if necessary, such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, aluminum chloride, ferrous chloride, ferric chloride, sodium bromide, odor. One or two kinds of metal halides such as potassium iodide, magnesium bromide, calcium bromide, iron bromide, nickel bromide, sodium iodide, potassium iodide, magnesium iodide, calcium iodide, iron iodide, etc. The above may be added. Moreover, adding a deodorant, a deodorant, and another functional filler is not restrict | limited at all. Further, the shape of the oxygen scavenger is not particularly limited, and may be any of powder, granule, lump, sheet, etc., or a sheet in which various oxygen absorbent compositions are dispersed in a thermoplastic resin or A film-like oxygen scavenger may be used.

  The above-described method can be adopted as a method for performing sterilization more easily and at low cost when the moisture content in the selectively permeable hollow fiber membrane is 5% by mass or more. When the moisture content is less than 5% by mass, use the selectively permeable hollow fiber membrane having the above-mentioned characteristics and optimize the oxygen concentration and humidity of the atmosphere surrounding the selectively permeable hollow fiber membrane during the radiation irradiation treatment. The method of doing is mentioned. Of course, even when the moisture content of the hollow fiber membrane is 5% by mass or more, there is no problem even if the method is additionally used. The first requirement in the method is a requirement relating to the oxygen concentration of the atmosphere surrounding the selectively permeable hollow fiber membrane during sterilization. It is preferable to perform radiation irradiation in a state where the oxygen concentration is 3.0% by volume or less. 1.0% by volume or less is more preferable, and 0.1% by volume or less is more preferable. If it exceeds 3.0% by volume, hydrogen peroxide production due to deterioration of polyvinyl pyrrolidone may increase and the above characteristics may not be satisfied.

The 2nd requirement in the said method is a requirement regarding the moisture content adsorb | sucked to the localized part of the polyvinyl pyrrolidone of a polysulfone type permselective hollow fiber membrane. When implemented by the above method, it is preferable to optimize the moisture content in the hollow fiber membrane and the humidity in the packaging bag. The water content is preferably 0.8% by mass or more. Moreover, it is preferable that the humidity in a packaging bag shall be over 40% RH as a relative humidity in 25 degreeC. The relative humidity of the space in the packaging bag is more preferably 50 to 90% RH (25 ° C.), and further preferably 60 to 80% RH (25 ° C.).
When the relative humidity of the space inside the packaging bag is 40% RH (25 ° C.) or lower, the hollow fiber membrane component is formed by a very small amount of oxygen gas even in the deoxygenated state when irradiated with radiation such as γ-ray irradiation. In particular, oxidative degradation of polyvinyl pyrrolidone occurs, and hydrogen peroxide is generated, leading to the above-described undesirable degradation reaction. Conversely, if the relative humidity exceeds 90% RH (25 ° C.), condensation may occur in the packaging bag, and the quality of the blood purifier may be reduced.

  The relative humidity referred to in the present invention is represented by the formula of relative humidity (% RH) = p / P × 100 using a water vapor partial pressure (p) at 25 ° C. and a saturated water vapor pressure (P) at 25 ° C. The measurement was performed by inserting and sealing a sensor of a temperature / humidity measuring device (Ondotori RH type, manufactured by T & D) into the packaging bag.

  The mechanism by which the deterioration of polyvinylpyrrolidone is suppressed by making the relative humidity of the space inside the packaging bag over 40% RH (25 ° C.) is presumed as follows. Degradation of polyvinyl pyrrolidone is accelerated by the presence of oxygen. In the present invention, the inside of the packaging bag is in a state in which oxidation is suppressed, that is, maintained in a substantially oxygen-free state, but a complete oxygen-free state is difficult, and a trace amount of oxygen gas is present. . Accordingly, the degradation reaction is promoted by the contact of polyvinyl pyrrolidone present on the surface of the hollow fiber membrane with this trace amount of oxygen gas present in the space inside the packaging bag. Therefore, the degradation reaction of polyvinyl pyrrolidone starts with polyvinyl pyrrolidone present on the surface of the hollow fiber membrane. Although the reason is unknown, it has been empirically recognized that the above degradation reaction is suppressed by increasing the water content in the hollow fiber membrane. The polyvinyl pyrrolidone present in the hollow fiber membrane is localized. Therefore, when the relative humidity in the packaging bag becomes high, water vapor existing in the packaging bag is selectively adsorbed on the localized portion of the polyvinyl pyrrolidone on the surface of the hollow fiber membrane, and the absorbed water deteriorates the polyvinyl pyrrolidone. It is considered that the reaction is suppressed. Therefore, it is presumed that a great suppression effect is expressed by increasing the humidity. On the other hand, it is known that a hollow fiber membrane containing polyvinylpyrrolidone has a humidity control function, that is, an absorption and desorption property (for example, JP-A-2004-97918). Therefore, when the relative humidity in the packaging bag is low, the moisture adsorbed on the polyvinylpyrrolidone present on the surface of the hollow fiber membrane is released to the space inside the packaging bag, and in particular, the polyvinylpyrrolidone present on the extreme surface subjected to the above-mentioned deterioration. It is presumed that the amount of adsorbed water becomes low and deterioration is promoted. It is presumed that the relative humidity in the packaging bag greatly affects the suppression of the degradation reaction of polyvinylpyrrolidone due to the synergistic effect of these phenomena.

As a method of satisfying the above two requirements, for example, a blood purifier filled with a polysulfone-based permselective hollow fiber membrane bundle containing polyvinylpyrrolidone having a water content of 0.8 to 600% by mass is combined with an oxygen scavenger along with oxygen permeation. degree is ^{10cm 3 / m 2 / 24h /} MPa (20 ℃, 90% RH) or less, the water vapor permeability of ^{50g / m 2 / 24h / MPa} (40 ℃, 90% RH) and sealed with packaging bag or less And a method of irradiating with radiation in a state where the relative humidity at 25 ° C. of the atmosphere in the packaging bag exceeds 40% RH.

  The oxygen scavenger used in the above method is used to absorb oxygen in the packaging bag and form a substantially deoxygenated state. Therefore, it is not limited as long as it has a deoxygenating function. For example, those described above are suitable.

The packaging bag used in the present invention needs to have a function of forming a space that is deoxygenated by the oxygen scavenger and maintaining the deoxygenated state for a long period of time. Therefore, it is necessary to be made of a material having a low oxygen gas permeability. Oxygen permeability ^{10cm 3 / m 2 / 24h /} MPa (20 ℃, 90% RH) preferably less. ^{8cm 3 / m 2 / 24h /} MPa (20 ℃, 90% RH) more preferably ^{less, 6cm 3 / m 2 / 24h} / MPa (20 ℃, 90% RH) more preferably less, 4cm ³ / m ² / 24 h / MPa (20 ° C., 90% RH) or less is more preferable.
Oxygen permeability ^{10cm 3 / m 2 / 24h /} MPa (20 ℃, 90% RH) If you exceed, even if sealed in the packaging bag, the oxygen gas is passed through from the packaging bag outside the packaging bag This is not preferable because the oxygen concentration increases and the substantial deoxygenation state cannot be maintained.

As described above, in the present invention, the hollow fiber membrane filled in the blood purifier needs to maintain a specific moisture content. Therefore, the packaging bag in the present invention is preferably made of a material having a low water vapor permeability. ^{50g / m 2 / 24h / MPa} (40 ℃, 90% RH) preferably less. ^{40g / m 2 / 24h / MPa} (40 ℃, 90% RH) more preferably ^{less, 30g / m 2 / 24h /} MPa (40 ℃, 90% RH) more preferably ^{less, 20g / m 2 / 24h /} MPa (40 ° C., 90% RH) or less is more preferable. ^{50g / m 2 / 24h / MPa} (40 ℃, RH 90%) If you exceed, even if sealed in the packaging bag, in order to pass steam through the packing bag, drying of the hollow fiber membrane progresses the This is not preferable because the preferable water content cannot be maintained.

  The material and configuration of the packaging bag used in the present invention are arbitrary without limitation as long as they have the characteristics described above. In a preferred embodiment, the material is made of an impermeable material for both oxygen gas and water vapor such as aluminum foil, aluminum vapor deposited film, inorganic oxide vapor deposited film such as silica and / or alumina, and vinylidene chloride polymer composite film. is there. Further, the sealing method in the packaging bag is not limited and is arbitrary, and examples thereof include a heat sealing method, an impulse sealing method, a fusing sealing method, a frame sealing method, an ultrasonic sealing method, and a high frequency sealing method. A composite material composed of a composite of the film material and the above-described impermeable material is preferable. In particular, both the impervious and heat-sealable functions, in which the outer layer is made of polyester film, the intermediate layer is made of aluminum foil, and the inner layer is made of polyethylene film, are made of aluminum foil that can substantially block oxygen gas and water vapor. It is preferable to apply a laminated sheet having the same.

  The method for setting the humidity in the packaging bag within the above range is not limited. For example, (1) When the blood purifier is sealed with a packaging bag, a humidity-controlled gas is injected into the packaging bag or sealed in a conditioned environment. (2) Depending on the moisture content of the selectively permeable hollow fiber membrane Examples include a method of adjusting, (3) using a deoxidizing agent that releases moisture, and (4) simultaneously sealing a humidity control agent together with the deoxidizing agent.

  The said humidity control agent will not be restrict | limited, if it has the characteristic which makes the relative humidity of the space in a packaging bag the said range by an absorption and moisture release function. As the humidity control agent, B-type silica gel is widely used, but is not limited. For example, as a humidity control agent similar to B-type silica gel, absorption and release can be achieved by sharpening the pore distribution of silica gel or by combining a humidity control agent composed of an alkali metal compound or an alkaline earth metal compound. Examples thereof include porous inorganic particles such as improved B-type silica gel, mesoporous silica alumina gel, mesoporous hollow aluminum silicate, zeolite and the like having improved wet characteristics. Also, particles composed of a water-absorbing polymer copolymerized, blended or alloyed with sodium acrylate cross-linked polymer, polyethylene glycol chain, polyvinyl pyrrolidone chain, etc., composite particles composed of the water-absorbing polymer combined with inorganic microcapsules, etc. May be. The shape of the humidity control agent is not particularly limited, and may be any of powder, granule, lump, sheet, and the like. It is preferable to use powdery and granular products by packaging them with a moisture-permeable packaging material. Moreover, you may use as a composite_body | complex combined with a film, a sheet | seat, paper, a nonwoven fabric, a woven fabric, etc. In this case, the composite substrate is preferably made of a hydrophilic material. Further, the humidity control agent particles may be combined with a hydrophilic binder and combined with a base material made of a general-purpose material such as polyester or polyolefin. In the case of a humidity control agent comprising a water-absorbing polymer, the polymer may be used directly as a film or sheet. Moreover, you may use in shapes, such as paper, a nonwoven fabric, and a woven fabric, as a fiber. Moreover, you may use it as a shape of a foam sheet or a home using a foaming agent. For example, humidity control sheets impregnated with water-absorbing sheets (paper, non-woven fabrics, woven fabrics) with inorganic salt humidity control agents such as ammonium chloride, water and surfactants, etc., sodium polyacrylate, inorganic materials such as magnesium metasilicate aluminate, etc. A sheet-like hydrogel fixed with a network-structured water-absorbing polymer crosslinked with a crosslinking agent can be suitably used.

  It is preferable to use the humectant after seasoning in an environment of 80 to 90% RH at 25 ° C. in advance.

  When implemented by the above method, the atmosphere around the hollow fiber membrane filled in the blood purifier needs to be maintained in a substantially deoxygenated state. Therefore, the opening of the blood purifier needs to be in an open state.

  The above-described method using deaerated water is referred to as a deaerated water method, and the method using an oxygen scavenger is referred to as an oxygen scavenger method.

  In the present invention, in the oxygen scavenger method, it is preferable to irradiate the radiation after sealing the packaging bag, and in the case of the degassing water method, after at least 48 hours have passed after sealing. . More preferably 72 hours or more. However, if the time until irradiation with radiation after sealing or sealing is too long, miscellaneous bacteria may grow. Therefore, it is preferable to perform the irradiation within 10 days after sealing or sealing. More preferably, it is within 7 days, and more preferably within 5 days. There is no limitation on the temperature at the time from sealing to irradiation with radiation, and it may be performed at room temperature, for example. If the irradiation treatment is performed in a state of less than 48 hours, the expression of water permeability performance during priming may be reduced.

  The reason why the expression of water permeability during priming changes depending on the elapsed time until irradiation treatment is unknown, but in the oxygen scavenger method, the trace amount of oxygen adsorbed on the hollow fiber membrane surface is deoxygenated. Desorption due to the deoxygenation effect of the agent, and in the case of the degassing water method, transfer to degassing water localized around the trace amount of oxygen adsorbed on the surface of the hollow fiber membrane. Thus, it is presumed that the deterioration is caused by suppressing the deterioration reaction that inhibits the affinity between the film surface and water caused by irradiation.

  As the radiation used in the present invention, α rays, β rays, γ rays, neutron rays, X rays, electron rays, ultraviolet rays, and ion beams are used. From the viewpoint of sterilization efficiency and ease of handling, γ rays or electron rays are used. Preferably used. The irradiation dose of radiation is not particularly limited as long as it can be sterilized and crosslinked, but generally 10 to 30 kGy is preferable.

  The oxygen scavenger method and the degassed water method described above have the following characteristics, respectively.

  The oxygen scavenger method can also be applied to a blood purifier filled with a low moisture content hollow fiber membrane having a moisture content of less than 5% by mass in the selectively permeable hollow fiber membrane, and is suitable for lightening. However, an oxygen scavenger is necessary, and the packaging bag needs to use a material having high oxygen and water vapor barrier properties, which is disadvantageous in terms of economy. On the other hand, the degassing water method is advantageous in terms of economy because it is not essential to use an oxygen scavenger and a general-purpose material can be used as the packaging bag. However, the moisture content in the selectively permeable hollow fiber membrane is required to be 5% by mass or more, which is disadvantageous in terms of weight reduction. Each has contradictory characteristics, and can be selected and used as appropriate according to market requirements. For example, in the case of products for extremely cold regions, the oxygen scavenger method is suitable.

  In the present invention, as described above, the elution of polyvinyl pyrrolidone from the hollow fiber membrane bundle is preferably 10 ppm or less.

  When the elution amount of polyvinylpyrrolidone exceeds 10 ppm, side effects and complications during long-term dialysis may occur due to the eluted polyvinylpyrrolidone. A method for satisfying the characteristics is not limited and can be achieved, for example, by setting the content of polyvinyl pyrrolidone to the polysulfone-based resin in the above range or optimizing the film forming conditions of the hollow fiber membrane bundle. More preferably, the elution amount of polyvinylpyrrolidone is 8 ppm or less, more preferably 6 ppm or less, and still more preferably 4 ppm or less. The elution amount of the polyvinyl pyrrolidone is determined by quantification using an extract extracted by a method according to the elution test method of the dialysis-type artificial kidney device manufacturing approval standard. That is, the hollow fiber membrane is arbitrarily taken out from the dried hollow fiber membrane bundle and weighed 1.0 g. The extract obtained by adding 100 ml of RO water to this and performing extraction at 70 ° C. for 1 hour is quantified.

  A measure for reducing the elution amount of the polyvinyl pyrrolidone is optional without limitation, but the content of polyvinyl pyrrolidone relative to the polysulfone resin and the hollow fiber so that the hydrogen peroxide elution amount and the surface concentration of polyvinyl pyrrolidone described above are satisfied at the same time. It is preferable to optimize the film forming conditions and the cleaning method of the film. It is also effective to crosslink by irradiation.

  In the blood purifier of the present invention, after the blood purifier is stored at room temperature for 1 year or more after irradiation, the hollow fiber membrane is taken out from the blood purifier and divided into approximately equal 10 parts for each of them. It is preferable that the maximum value of UV (220 to 350 nm) absorbance in the hollow fiber membrane extract when the test defined by the manufacturing approval standard is performed is 0.10 or less at all sites. More preferably, the characteristics are maintained even after two years or more. Since the warranty period of the blood purifier is set to 3 years, it is particularly preferable that the characteristics are maintained for at least 3 years. It has been empirically confirmed that if the maximum value of UV (220 to 350 nm) absorbance is maintained at 0.06 or less after 1 year, it can be maintained for 3 years.

When used for the blood purifier, it is preferable that the burst pressure is made of a hollow fiber membrane bundle having a pressure of 0.5 MPa or more and that the water permeability of the blood purifier is 150 ml / m ² / hr / mmHg or more. If the burst pressure is less than 0.5 MPa, there is a possibility that it is impossible to detect a potential defect that leads to a blood leak as described later. Moreover, if the water permeability is less than 150 ml / m ² / hr / mmHg, the dialysis efficiency may decrease. In order to increase the dialysis efficiency, the pore diameter is increased or the number of pores is increased. However, this tends to cause a problem that the membrane strength is reduced or defects are formed. Therefore, it is preferable that the porosity of the support layer portion is optimized by optimizing the pore diameter of the outer surface, and the solute permeation resistance and membrane strength are balanced. A more preferable range of water permeability is 200 ml / m ² / hr / mmHg or more, more preferably 250 ml / m ² / hr / mmHg or more, and still more preferably 300 ml / m ² / hr / mmHg or more. In addition, when the water permeability is too high, it becomes difficult to control water removal during hemodialysis, and therefore, 2000 ml / m ² / hr / mmHg or less is preferable. More preferably 1800ml / m ² / hr / mmHg or less, more preferably 1500ml / m ² / hr / mmHg or less, still more preferably not more than ^{1300ml / m 2 / hr / mmHg} .

Usually, a blood purifier used for blood purification is subjected to a leak test in which the inside or outside of the hollow fiber membrane is pressurized with air in order to confirm defects in the hollow fiber membrane or the blood purifier at the final stage of production. When a leak is detected by the pressurized air, the blood purifier is discarded as a defective product, or an operation for repairing the defect is performed. The air pressure in this leak test is often several times the guaranteed pressure resistance of the hemodialyzer (usually 500 mmHg (0.067 MPa)). However, in the case of a hollow fiber type blood purification membrane having a particularly high water permeability, minute scratches, crushing, and tearing of the hollow fiber membrane that cannot be detected by a normal pressure leak test are caused by manufacturing processes (mainly sterilization) after the leak test. And packaging), transportation process, or handling in clinical settings (unpacking, priming, etc.), which leads to the cutting of hollow fiber membranes and pinholes, which in turn causes troubles of blood leaking during treatment. is required. The trouble can be avoided by setting the burst pressure to the above characteristic.
Further, the uneven thickness of the hollow fiber membrane bundle is effective for suppressing the occurrence of the above-described potential defects.

  The burst pressure in the present invention is an index of pressure resistance of the hollow fiber membrane bundle after the hollow fiber membrane is made into a blood purifier. The inside of the hollow fiber membrane bundle is pressurized with gas, and the pressure is gradually increased. The pressure when the hollow fiber membrane burst without being able to withstand the internal pressure. The higher the burst pressure, the less the cutting of the hollow fiber membrane bundle and the generation of pinholes during use, so 0.5 MPa or more is preferable, 0.55 MPa or more is more preferable, and 0.6 MPa or more is even more preferable. If the burst pressure is less than 0.5 MPa, there may be a potential defect. The higher the burst pressure, the better. However, if the focus is on increasing the burst pressure and the film thickness is increased or the porosity is decreased too much, the desired film performance may not be obtained. Therefore, when finished as a hemodialysis membrane, the burst pressure is preferably less than 2.0 MPa. More preferably, it is less than 1.7 MPa, more preferably less than 1.5 MPa, still more preferably less than 1.3 MPa, and particularly preferably less than 1.0 MPa.

  The uneven thickness in the present invention is a thickness deviation when observing 100 cross sections of hollow fiber membrane bundles in the hollow fiber membrane bundle blood purifier, and is represented by a ratio between a maximum value and a minimum value. The minimum thickness deviation of 100 hollow fiber membranes is preferably 0.6 or more. If even one hollow fiber membrane with a thickness deviation of less than 0.6 is included in 100 hollow fiber membranes, the hollow fiber membrane may cause a leak during clinical use. It represents not the value but 100 minimum values. Higher unevenness increases the uniformity of the film, suppresses the appearance of latent defects and improves the burst pressure, more preferably 0.7 or more, more preferably 0.8 or more, still more preferably 0.85 or more. If the uneven thickness is too low, latent defects are likely to be manifested, the burst pressure is lowered, and blood leakage is liable to occur.

  As an achievement means for making the unevenness degree 0.6 or more, for example, it is preferable to make the slit width of the nozzle that is the discharge port of the film forming solution strictly uniform. The spinning nozzle of the hollow fiber membrane bundle is generally a tube-in-orifice type nozzle having an annular part for discharging the spinning solution and a core liquid discharge hole serving as a hollow forming agent inside thereof. The width of the outer annular portion that discharges the spinning solution. By reducing the variation in the slit width, the uneven thickness of the spun hollow fiber membrane bundle can be reduced. Specifically, the ratio between the maximum value and the minimum value of the slit width is 1.00 or more and 1.11 or less, and the difference between the maximum value and the minimum value is preferably 10 μm or less, more preferably 7 μm or less, More preferably, it is 5 micrometers or less, More preferably, it is 3 micrometers or less. It is also a preferred embodiment to optimize the nozzle temperature. The nozzle temperature is preferably 20 to 100 ° C. If it is less than 20 ° C., it is easily affected by the room temperature, the nozzle temperature is not stable, and the discharge spots of the spinning solution may occur. Therefore, the nozzle temperature is more preferably 30 ° C. or higher, further preferably 35 ° C. or higher, and further preferably 40 ° C. or higher. On the other hand, when the temperature exceeds 100 ° C., the viscosity of the spinning solution may be too low and ejection may become unstable, and thermal degradation / decomposition of polyvinylpyrrolidone may progress. Therefore, the nozzle temperature is more preferably 90 ° C. or less, further preferably 80 ° C. or less, and still more preferably 70 ° C. or less.

  Furthermore, as a measure for increasing the burst pressure, it is also an effective method to reduce potential defects by reducing flaws on the surface of the hollow fiber membrane bundle, foreign matters and bubbles. As a method of reducing the occurrence of scratches, the material and surface roughness of rollers and guides in the manufacturing process of the hollow fiber membrane bundle are optimized, and when the hollow fiber membrane bundle is inserted into the blood purifier container when the blood purifier is assembled. It is effective to devise such that contact between the container and the hollow fiber membrane bundle or rubbing between the hollow fiber membrane bundles is reduced. In the present invention, it is preferable to use a roller having a mirror-finished surface in order to prevent the hollow fiber membrane bundle from slipping and scratching the surface of the hollow fiber membrane bundle. In addition, it is preferable to use a guide whose surface is textured or knurled in order to avoid contact resistance with the hollow fiber membrane bundle as much as possible. When the hollow fiber membrane bundle is inserted into the blood purifier container, the hollow fiber membrane bundle is not directly inserted into the blood purifier container, but the contact surface with the hollow fiber membrane bundle is hollowed, for example, with a satin finish. It is preferable to use a method in which a wound film bundle is inserted into a blood purifier container, and after insertion, only the film is removed from the blood purifier container.

  As a method for suppressing the mixing of foreign matter into the hollow fiber membrane bundle, a method using a raw material with little foreign matter, filtering a spinning solution for film formation, and reducing foreign matter is effective. In the present invention, it is preferable to filter the spinning solution using a filter having a pore size smaller than the film thickness of the hollow fiber membrane bundle and then discharge from the nozzle. Specifically, the uniformly dissolved spinning solution is discharged from the dissolution tank to the nozzle. It passes through a sintered filter having a pore diameter of 10 to 50 μm provided during the introduction. The filtration process may be performed at least once. However, in the case where the filtration process is performed in several stages, it is preferable to reduce the pore diameter of the filter as it becomes the latter stage in order to extend the filtration efficiency and the filter life. The pore size of the filter is more preferably 10 to 45 μm, further preferably 10 to 40 μm. If the filter pore size is too small, the back pressure may increase and the quantitativeness may decrease. Further, as a method for suppressing the mixing of bubbles, it is effective to defoam a polymer solution for film formation. Depending on the viscosity of the spinning solution, static defoaming or vacuum defoaming can be used. In this case, after the inside of the dissolution tank is depressurized to −100 to −750 mmHg, the inside of the tank is sealed and allowed to stand for 5 to 30 minutes. This operation is repeated several times to perform defoaming treatment. If the degree of vacuum is too low, the treatment may take a long time because it is necessary to increase the number of defoaming times. On the other hand, when the degree of vacuum is too high, the cost for increasing the degree of sealing of the system may increase. The total treatment time is preferably 5 minutes to 5 hours. If the treatment time is too long, polyvinylpyrrolidone may be decomposed and deteriorated due to the effect of reduced pressure. If the treatment time is too short, the defoaming effect may be insufficient.

  Hereinafter, the effectiveness of the present invention will be described with reference to examples, but the present invention is not limited thereto. In addition, the evaluation method of the physical property in the following examples is as follows.

1. Measurement of water permeability The blood outlet circuit of the dialyzer (the outlet side from the pressure measurement point) is sealed with forceps and is subjected to total filtration. Purified water kept at 37 ° C is put into a pressurized tank, and the pressure is controlled by a regulator. The pure water is sent to a dialyzer kept warm in a 37 ° C constant temperature bath, and the amount of filtrate flowing out from the dialysate side is measured with a graduated cylinder. To do. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2
And Here, Pi is the dialyzer inlet side pressure, and Po is the dialyzer outlet side pressure. The TMP is changed at four points, the filtration flow rate is measured, and the water permeability (mL / hr / mmHg) is calculated from the slope of the relationship. At this time, the correlation coefficient between TMP and the filtration flow rate must be 0.999 or more. In order to reduce the pressure loss error due to the circuit, TMP is measured in the range of 100 mmHg or less. The water permeability of the hollow fiber membrane bundle is calculated from the membrane area and the water permeability of the dialyzer.
UFR (H) = UFR (D) / A
Here, UFR (H) is the water permeability of the hollow fiber membrane bundle (mL / m ² / hr / mmHg), UFR (D) is the water permeability of the dialyzer (mL / hr / mmHg), and A is the membrane area of the dialyzer. (M ² ).

2. Calculation of membrane area The membrane area of the dialyzer is obtained as a reference for the inner diameter of the hollow fiber membrane.
A = n × π × d × L
Here, n is the number of hollow fiber membranes in the dialyzer, π is the circumference, d is the inner diameter (m) of the hollow fiber membrane, and L is the effective length (m) of the hollow fiber membrane in the dialyzer.

3. Burst pressure Fill the dialysis solution side of a blood purifier consisting of about 10,000 hollow fiber membrane bundles with water and plug it. Dry air or nitrogen is fed from the blood side at room temperature and pressurized at a rate of 0.5 MPa per minute. The pressure is increased, and the air pressure when the hollow fiber membrane bundle bursts (bursts) with pressurized air and bubbles are generated in the liquid filled on the dialysate side is defined as the burst pressure.

4. Unevenness of thickness The cross section of 100 hollow fiber membranes is observed with a 200 times projector. In one field of view, the thickness of the thickest part and the thinnest part is measured with respect to one yarn cross section having the largest film thickness difference.
Thickness unevenness = thinnest part / thickest part thickening degree = 1, and the film thickness is perfectly uniform.

5. Elution amount of polyvinyl pyrrolidone Extracted by the method defined in the dialysis artificial kidney device production standard, and polyvinyl pyrrolidone in the extract was quantified by a colorimetric method.
In the case of a dry hollow fiber membrane blood purifier, 100 ml of pure water is added to 1 g of a hollow fiber membrane bundle and extracted at 70 ° C. for 1 hour. The obtained extract (2.5 ml), 0.2 molar aqueous citric acid solution (1.25 ml) and 0.006 normal iodine aqueous solution (0.5 ml) were mixed well and allowed to stand at room temperature for 10 minutes, and the absorbance at 470 nm was measured. Quantification was performed with a calibration curve obtained by measuring according to the above method using a standard polyvinylpyrrolidone.
In the case of the wet hollow fiber membrane blood purifier, physiological saline was passed through the dialysate side flow path of the blood purifier at 500 mL / min for 5 minutes, and then passed through the blood side flow path at 200 mL / min. Thereafter, the solution was passed from the blood side to the dialysate side while filtering at 200 mL / min for 3 minutes, and then freeze-dried to obtain a dry membrane, and the above-described quantification was performed using the dry membrane.

6. UV (220-350 nm) Absorbance Absorbance in the wavelength range of 200 to 350 nm using a spectrophotometer (manufactured by Hitachi, U-3000) of the extract extracted by the method defined in the dialysis-type artificial kidney device manufacturing approval standard And the maximum absorbance in this wavelength range was determined.
In this measurement, the hollow fiber membrane bundle was equally divided into 10 pieces in the longitudinal direction, and 1 g of the hollow fiber membrane bundle in a dry state was weighed from each part and measured for all samples.
In the case of a wet hollow fiber membrane blood purifier, measurement was performed using a dry membrane obtained by processing in the same manner as the measurement of the amount of polyvinylpyrrolidone eluted.

7. Quantitative determination of hydrogen peroxide TiCl ₄ mixed in an equimolar ratio with an ammonium chloride buffer solution (PH 8.6) 0.2 ml in 2.6 ml of the extract extracted by the method defined in the dialysis artificial kidney device manufacturing approval standard A mixture of a hydrogen chloride solution of 4- (2-pyridylazo) resorcinol with an aqueous Na salt solution was added, 0.2 ml of a coloring reagent prepared to 0.4 mM was further added, and the mixture was heated at 50 ° C. for 5 minutes, and then brought to room temperature. After cooling, the absorbance at 508 nm was measured. A quantitative value was obtained using a calibration curve obtained by measuring in the same manner using a sample.
In this measurement, the hollow fiber membrane bundle was equally divided into 10 pieces in the longitudinal direction, and 1 g of the hollow fiber membrane bundle in a dry state was weighed from each part and measured for all samples.
In the case of a wet hollow fiber membrane blood purifier, measurement was performed using a dry membrane obtained by processing in the same manner as the measurement of the amount of polyvinylpyrrolidone eluted. Moreover, when quantifying about the hollow fiber membrane bundle in a wet state, it measured about the dry membrane obtained by drying by the freeze-dry method.

8. Blood Leak Test A 37 ° C. bovine blood to which citric acid is added and coagulation is suppressed is fed to a blood purifier at 300 mL / min, and the blood is filtered at a rate of 90 mL / min. At this time, the filtrate is returned to blood to be a circulatory system. After 60 minutes, the filtrate from the blood purifier is collected, and the red color resulting from red blood cell leakage is visually observed. In this blood leak test, 30 blood purifiers were used in each Example and Comparative Example, and the number of blood purifiers that had leaked blood was examined.

9. Maximum protrusion height on the inner surface of the hollow fiber membrane (PV value)
Ten arbitrary hollow fiber membranes were selected from a bundle consisting of a plurality of hollow fiber membranes, and each hollow fiber membrane was measured at an arbitrary one place by 0.1 mm, and the average degree of unevenness was determined. The measurement was performed using a scanning white interference microscope (NewView 100) manufactured by ZYGO, using a 20 × objective lens under the conditions of a system magnification of 2 times, and the average value was displayed. The measurement was performed without using a filter.

10. Storage stability of hollow fiber membrane bundles The dried hollow fiber membrane bundles obtained in each of the examples and comparative examples were kept in a dry box (atmosphere was air) adjusted to a humidity of 50% RH for 3 months. After storage, UV (220-350 nm) absorbance was measured by a method defined in the dialysis artificial kidney device manufacturing approval standard. Stability was determined by the degree of increase in UV (220-350 nm) absorbance due to the storage. The degree of increase was obtained by equally dividing the hollow fiber membrane bundle into 10 pieces in the longitudinal direction, measuring each sample, and determining the maximum value. Those whose maximum value did not exceed 0.10 were considered acceptable.

11. Measurement of oxygen concentration in packaging bag and water Measurement of oxygen concentration in the packaging bag was performed by gas chromatography. A column packed with molecular sieve (Molecular sieve 13X-S mesh 60/80 manufactured by GL Science) was used, the carrier gas was analyzed using argon gas, the detector was analyzed using a heat conduction method, and the column temperature was 60 ° C. The gas in the packaging bag was collected by piercing the syringe needle directly into the unopened packaging bag.
The oxygen concentration in water was measured using a dissolved oxygen meter OM-51-L1 manufactured by HORIBA.

12. Measurement of inner diameter and film thickness of hollow fiber membrane The hollow fiber membrane is cut with a sharp razor perpendicular to the length direction, and the cross section is observed with a microscope at a magnification of 200 times. The inner diameter value and the outer diameter value are measured at n = 5, and the average value is calculated.
Film thickness [μm] = {(outer diameter) − (inner diameter)} / 2

13. Adsorption rate of methylene blue The adsorption rate of methylene blue on the hollow fiber membrane was calculated from the concentration of methylene blue in the solution before and after perfusion of the methylene blue solution by the following method.
(1) A methylene blue solution is prepared by dissolving methylene blue in water to a concentration of 0.5 ppm.
(2) Sampling the methylene blue solution before contact with the membrane.
(3) Measure 1000 ml of methylene blue solution and fill the blood side and dialysate side of the hollow fiber membrane blood purifier with a membrane area of 1.5 m ² .
(4) After filling the blood purifier, pool the excess methylene blue solution and perfuse the blood side of the blood purifier at a flow rate of 200 mL / min. At this time, a circuit is constructed so that the solution flowing out of the solution pool passes through the blood side of the blood purifier and returns to the pool.
(5) After perfusion for 5 minutes, the methylene blue solution filled in the blood purifier and the pooled methylene blue solution are combined and sampled.
(6) A calibration curve is created from the absorbance at the maximum absorption wavelength of 490 nm in the ultraviolet absorption spectrum of the methylene blue aqueous solution, and the concentration of the methylene blue solution before and after contact with the membrane is measured.
(7) The methylene blue adsorption rate is calculated from the following equation.
(Methylene blue adsorption rate) [%] = 100 × (methylene blue concentration of solution after perfusion) / (methylene blue concentration of solution before perfusion)

14. Measurement of specific resistance The specific resistance of water is calculated from the electric conductivity measured with an electric conductivity meter (CM-40V, manufactured by Toa Radio Industry Co., Ltd.).
(Resistivity) [MΩcm] = 1 / (Electric conductivity)

15. Storage stability of blood purifier After storing the blood purifier after irradiation for one year at room temperature, UV (220-350 nm) absorbance was measured by the method described above. Stability was determined by the degree of increase in UV (220-350 nm) absorbance due to the storage. The degree of increase was obtained by equally dividing the hollow fiber membrane bundle into 10 pieces in the longitudinal direction, measuring each sample, and determining the maximum value. Those whose maximum value did not exceed 0.10 were considered acceptable.

16. Moisture content of hollow fiber membrane The moisture content of the hollow fiber membrane was measured by measuring the mass (g) of the hollow fiber membrane before drying, and then performing vacuum drying under reduced pressure (-750 mmHg or less) for 12 hours, after drying The mass (g) of the hollow fiber membrane is measured. The mass difference between before and after drying is determined as a weight loss (g) in% based on the mass after drying (g). The moisture content is determined by the following formula.
(Weight loss / mass after drying) × 100 = moisture content (mass%)
Here, by setting the mass of the hollow fiber membrane within the range of 1 to 2 g, it can be in an absolutely dry state (a state in which there is no further mass change) after 2 hours.

17. Content of polyvinyl pyrrolidone in the outermost layer on the inner and outer surfaces of the hollow fiber membrane The content of polyvinyl pyrrolidone was determined by X-ray photoelectron spectroscopy (ESCA method).
One hollow fiber membrane was cut obliquely with a razor so that a part of the inner surface was exposed, and was attached to a sample stage so that the inner and outer surfaces could be measured, and measurement was performed by ESCA. The measurement conditions are as follows.
Measuring device: ULVAC-Phi ESCA5800
Excitation X-ray: MgKα ray X-ray output: 14 kV, 25 mA
Photoelectron escape angle: 45 °
Analysis diameter: 400μmφ
Pass energy: 29.35 eV
Resolution: 0.125 eV / step
Degree of vacuum: about 10 ⁻⁷ Pa or less From the measured value (N) of nitrogen and the measured value (S) of sulfur, the polyvinylpyrrolidone content on the surface was calculated by the following formula.
<Polyvinylpyrrolidone-added PES (polyethersulfone) membrane>
Polyvinylpyrrolidone content (H polyvinylpyrrolidone) [mass%]
= 100 × (N × 111) / (N × 111 + S × 232)
<Polyvinylpyrrolidone-added PSf (polysulfone) membrane>
Polyvinylpyrrolidone content (H polyvinylpyrrolidone) [mass%]
= 100 × (N × 111) / (N × 111 + S × 442)

18. Polyvinylpyrrolidone content in the entire hollow fiber membrane The hollow fiber membrane was dried at 80 ° C. for 48 hours using a vacuum dryer, and 10 mg of the membrane was obtained using a CHN coder (manufactured by Yanaco Analytical Industries, Model MT-6). Analysis was performed, and the content of polyvinylpyrrolidone was calculated from the nitrogen content by the following formula.
Polyvinylpyrrolidone content (mass%) = nitrogen content (mass%) × 111/14

19. Diameter of aggregated particles, standard deviation A cross-section obtained by freezing a hollow fiber membrane after freezing in liquid nitrogen is coated with an osmium plasma, and then a frozen section photograph (magnification: 4) using a field emission scanning electron microscope. 100 to 70,000 times), 100 aggregated particles in the dense layer were measured, and the average diameter and standard deviation were calculated. The particle diameter was the average value of the major axis and minor axis of each particle. In addition, from the innermost surface toward the outer surface of the membrane, about 10 particles were measured from the size of the aggregated particles. (For example, when the particle diameter is 50 nm, an internal dense layer corresponding to 500 nm from the film surface is used as the measurement region.)

20, Bovine blood adjusted to 37 ° C., hematocrit (Ht) 40 ± 2.0%, total protein concentration 6.5 ± 0.5 g / dl on a hollow fiber membrane module with a β2-microglobulin sieve coefficient of 1.5 m ^2. The blood was flowed to the blood side at 300 ml / min, and the blood and filtrate at the inlet and outlet of the module at the time of 15 minutes and 120 minutes after the start of blood filtration at a filtration rate of 90 ml / min were sampled, and an enzyme immunoassay (for example, Grazyme β2 -The concentration of β2-microglobulin (hereinafter abbreviated as β2-MG) is measured by Microglobulin-EIA Test Wako Pure Chemical Industries. It should be noted that an appropriate amount of human-derived β2-MG is added to the bovine blood flowing through the module in this measurement, and the sampled blood is centrifuged as necessary to be used for β2-MG measurement. From these β2-MG concentration values, a β2-MG sieving coefficient (hereinafter referred to as SC) is obtained according to the following formula.
SC = Cfil / ((CI + CO) / 2)
Cfil: β2-MG concentration of filtrate CI: β2-MG concentration of blood at the module blood side inlet CO: β2-MG concentration of blood at the module blood side outlet

21, Screening coefficient of albumin (SC)
The same experiment as the measurement of β2 microglobulin shown above was performed, and after 15 minutes from the start of filtration, blood and filtrate were sampled at the inlet and outlet of the module, and the albumin concentration of each liquid was measured by the bromocresol green method. . From these concentration values, the sample concentration in the above formula is defined as the albumin concentration, and SC is determined.

22. Performance expression during priming Saline was flowed from the blood side inlet port of the blood purifier, and the water permeability after 10 minutes and 24 hours was evaluated by the above evaluation method, and 10 minutes with respect to the water permeability after 24 hours. The ratio of the water permeability after was calculated | required, and the following references | standards determined. After measuring the water permeability after 10 minutes, the blood purifier was filled with water and kept at room temperature for up to 24 hours.
90% or more: ○
Less than 90%: ×

Example 1
In a kneading and dissolving machine that expresses a kneading effect by so-called planetary motion in which two frame-type blades rotate and revolve, 1 part by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (registered trademark) 4800P), 0.175 parts by mass of polyvinylpyrrolidone (BASF Koridone (registered trademark) K90) and 1 part by mass of dimethylacetamide (DMAc) were charged, and the mixture was stirred for 2 hours and kneaded. Subsequently, a mixed solution of 3.02 parts by mass of DMAc and 0.16 parts by mass of RO water was added over 1 hour. Stirring was continued for an additional hour by increasing the number of revolutions of the stirrer and dissolved uniformly. At this time, kneading and dissolution were performed in a nitrogen atmosphere. The temperature during kneading and dissolution was cooled so as not to exceed 40 ° C. The stirring fluid number and stirring Reynolds number at the final dissolution were 1.0 and 100, respectively. Subsequently, the film forming solution was defoamed. After the defoaming was completed, the inside of the system was again purged with nitrogen and maintained in a weakly pressurized state. The polyvinyl pyrrolidone having a hydrogen peroxide content of 130 ppm was used. The membrane-forming solution was passed through a two-stage sintered filter of 15 μm and 15 μm in order, and then simultaneously discharged together with a 60 mass% DMAc aqueous solution degassed as a hollow forming agent from a tube-in orifice nozzle heated to 50 ° C. After passing through a 400 mm dry section cut off from the outside air by a tube, it was coagulated in a 20 mass% DMAc aqueous solution at 75 ° C., and was rolled up in a wet state. The tube-in-orifice nozzle used had a center hole diameter of 100 μm, a film forming solution draft ratio of 1.04, and an absolute humidity of the dry part of 0.11 kg / kg dry air. The linear velocities immediately after discharge were 17910 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.7. All the water used in the spinning process was RO water. The specific resistance was 1.1 MΩcm. During the spinning process, all the rollers with which the hollow fiber membrane bundle contacts were mirror-finished on the surface, and the guides were all finished with a satin finish. These guides and rollers were surface-treated with Teflon (registered trademark). Moreover, mist-like water was sprayed on the hollow fiber membrane bundle under running just before winding. A polyethylene film is wound around a bundle of about 10,000 hollow fiber membranes, then cut to a length of 27 cm (hereinafter referred to as a bundle), and washed in water at 121 ° C. for 30 minutes × 3 times. Excess polyvinylpyrrolidone, solvent, and endotoxin (fragment) contained in the membrane were removed.

The obtained wet hollow fiber membrane bundle was introduced into a microwave dryer having an exhaust system for reducing the pressure of the far infrared heater and the oven, and dried under the following conditions. After heating the hollow fiber membrane bundle for 30 minutes under a reduced pressure of 7 kPa with an output of 1.5 kW, the microwave irradiation was stopped and at the same time, the reduced pressure was 1.5 kPa and maintained for 3 minutes. (First stage). Subsequently, the degree of vacuum was returned to 7 kPa, the microwave was irradiated and the hollow fiber membrane bundle was heated at an output of 0.5 kW for 10 minutes, then the microwave was cut and the degree of vacuum of 0.7 kPa was maintained for 3 minutes. (Second stage). Furthermore, the degree of vacuum was returned to 7 kPa, and microwave irradiation was performed for 8 minutes at an output of 0.2 kW to heat the hollow fiber membrane bundle. (3rd stage). After the microwave cutting, the degree of vacuum was set to 0.5 kPa, and only the far infrared rays were irradiated for 10 minutes to complete the drying of the hollow fiber membrane bundle.
The maximum temperature reached on the surface of the hollow fiber membrane bundle during the drying period was 65 ° C. The moisture content of the hollow fiber membrane bundle before drying is 350% by mass, the moisture content of the hollow fiber membrane bundle after the first stage is 35% by mass, and the moisture content of the hollow fiber membrane bundle after the second stage is 12% by mass. The water content of the hollow fiber membrane bundle after the third stage was 3.2% by mass. The obtained hollow fiber membrane had an inner diameter of 200.3 μm, a film thickness of 29.0 μm, a moisture content of 2.4% by mass, and a content of polyvinyl pyrrolidone with respect to polyethersulfone was 3.2% by mass. Some of these manufacturing conditions are shown in Table 1.

  The hollow fiber membrane obtained in this example has a dense layer on the inner surface, and the dense layer comprises an aggregate of aggregated particles, the average particle diameter of the aggregated particles is 108 nm, and the particle diameter of the aggregated particles The standard deviation of the distribution was 32 nm (0.3 times the average particle size).

  The obtained hollow fiber membrane bundle was equally divided into 10 pieces in the longitudinal direction, and 1 g of the hollow fiber membrane bundle in a dry state was weighed from each portion, and the amount of hydrogen peroxide eluted was measured. Hydrogen peroxide was stable at low levels at all sites. The obtained hollow fiber membrane bundle was stored in a dry state. Even after storage for 3 months, the maximum value of UV (220-350 nm) absorbance, which is the standard for approval of dialysis-type artificial kidney device manufacture for hollow fiber membrane bundles, is 0.04, and the standard value of 0.10 or less is maintained. The storage stability was good. The quantitative values are shown in Tables 3 and 4.

The obtained hollow fiber membrane bundle was loaded into a blood purifier container at a filling rate of 60% by volume, the ends were bonded with urethane resin, the resin was cut out, and the hollow fiber membrane end was opened to assemble the blood purifier. . At the time of this loading operation, the bundle to be inserted was previously subjected to a charge removal process using a charge removal blower (charge removal blower SJ-F020 manufactured by Keyence Corporation). In addition, the loading of the bundle and the film removal operation were performed in the same static elimination environment. As a result of conducting a leak test of the obtained blood purifier, no adhesion failure caused by the sticking of the hollow fiber membranes was observed. The blood purifier is composed of two general-purpose oxygen scavengers (Tamotsu (registered trademark) manufactured by Oji Tac Co., Ltd.), a pore volume of 1.05 cc / g, a surface area of 320 m ² / g, and a silica gel having a particle size of 8 mesh and calcium chloride. An oxygen transmission rate and a water vapor transmission rate of 1 cm ³ / m ² each consisting of a modified silica gel B loaded with 10% by mass of a silica gel B in a paper pack and an outer layer made of polyester film, an intermediate layer made of aluminum foil, and an inner layer made of polyethylene film. / 24h / MPa (20 ℃, 90% RH) or less, and ^{5g / m 2 / 24h / MPa} (40 ℃, 90% RH) was sealed and sealed by heat sealing method under the following aluminum laminated sheet consisting of the packaging bag. The humidity conditioner used was seasoned in advance in an environment with a relative humidity of 85% RH for 24 hours. The package was stored at room temperature for 72 hours and then sterilized by irradiation with 25 kGy of γ rays. The oxygen concentration in the packaging bag of the package sealed simultaneously with the sterilized product was measured. It was substantially oxygen-free at 0.1% by volume or less. The relative humidity was 75% RH.

  A plurality of blood purifiers were produced. The hollow fiber membrane was taken out from the completed blood purifier, and the surface roughness of the inner surface of the hollow fiber membrane was measured. The maximum protrusion height (PV value) was 0.10 μm, and the smoothness of the inner surface was good. In addition, a micro blood purifier was made by bundling 10 extracted hollow fiber membranes, and a blood compatibility test and a methylene blue adsorption rate were measured. The methylene blue adsorption rate has an appropriate value, negative charge control is appropriate, and as described above, the particle size of the aggregated particles of the inner dense layer, the standard deviation of the particle size distribution, and the smoothness of the surface are appropriate. The selective separability and its stability over time were good. In addition, the UV absorbance (220-350 nm) did not deteriorate even after γ-ray irradiation, and the standard value of 0.1 for the dialysis artificial kidney device production approval reference test was maintained. Moreover, the increase in the hydrogen peroxide elution amount in the hollow fiber membrane was not observed. Therefore, the storage stability of the blood purifier obtained in this example is good, and UV, which is a manufacturing approval standard for a dialysis artificial kidney device for a bundle of hollow fiber membranes filled in the blood purifier after storage for one year. The maximum value of (220-350 nm) absorbance was 0.05, and the standard value of 0.10 or less was maintained.

When the hollow fiber membrane was taken out from the blood purifier and the outer surface was observed with a microscope, no defects such as scratches were observed. In addition, citrated fresh cow blood was flowed to the blood purifier at a blood flow rate of 300 mL / min and a filtration rate of 90 mL / min / m ² , but no blood cell leak was observed. In addition, the blood purifier has good water permeability at the time of priming, and is highly practical as a blood purifier.

  These evaluation results are shown in Table 4.

(Comparative Examples 1 and 2)
In Example 1, the hollow fiber membrane bundle and blood purifier of Comparative Examples 1 and 2 were obtained in the same manner as in Example 1 except that the following changes were made.
(1) The nozzle temperature was changed to 65 ° C., (2) the central hole diameter of the nozzle was changed to 180 μm, (3) the hollow forming agent discharge linear velocity was changed to 11620 and 55660 cm / min, respectively, and the linear velocity ratio was changed to 2.4 and 11 respectively. (4) Dry part length to 600 mm, (5) DMAc concentration in the hollow forming agent to 35% by mass, (6) Draft ratio to 2.45, (7) All used in spinning process The tap water was changed to tap water, and (8) the charge removal process at the time of loading the hollow fiber membrane bundle into the blood purifier container was omitted. Some of these manufacturing conditions are shown in Table 2. Tables 3 and 5 show the evaluation results of the hollow fiber membrane and the blood purifier, respectively.
The blood purifiers obtained in both comparative examples were poor in separability over time in selective separation. The hollow fiber membranes filled in the blood purifiers obtained in these comparative examples are not suitable for the film-forming conditions, and the particle diameter of the aggregated particles of the dense layer on the inner surface of the hollow fiber membrane and the standard of the particle size distribution thereof The deviation is not appropriate, and the hollow fiber membrane bundle obtained in Comparative Example 1 has a low linear velocity ratio of 2.5 times immediately after discharge, and the friction at the interface between the membrane forming solution and the hollow forming agent is sufficient. It is thought that the contribution of not being able to control to an appropriate negative charge was great. On the other hand, in the hollow fiber membrane bundle obtained in Comparative Example 2, the ratio of the linear velocity immediately after discharge is as high as 11.5 times in addition to the above problems, and the friction at the interface between the membrane forming solution and the hollow forming agent is excessive. In addition, it was impossible to control the negative charge appropriately, and stable spinning could not be performed, so a uniform hollow fiber membrane could not be obtained, and the contribution of the deterioration of the surface smoothness of the inner surface was significant. It is thought.

(Comparative Example 3)
In Comparative Example 1, polyvinyl pyrrolidone having a hydrogen peroxide content of 500 ppm was used as a raw material, the kneading and dissolution temperature was 85 ° C., nitrogen gas replacement in the raw material supply system and dissolution tank was stopped, and the number of washings of the hollow fiber membrane bundle was 1 Comparative Example 1 except that the wet and selectively permeable hollow fiber membrane bundle was changed to dry under a normal pressure by irradiating with microwaves until the water content became 0.5% by mass. Similarly, a selectively permeable hollow fiber membrane bundle and a blood purifier were obtained. Tables 3 and 5 show the characteristics of the obtained selectively permeable hollow fiber membrane bundle and blood purifier. The permselective hollow fiber membrane bundle obtained in this comparative example had a large amount of hydrogen peroxide elution, and the permselective hollow fiber membrane bundle storage stability was inferior. Further, the UV (220-350 nm) absorbance was high and varied greatly depending on the sampling location, and although it was mild, partial sticking occurred and the workability of the blood purifier assembly was not good. In addition to the problem of the blood purifier obtained in Comparative Example 1, the blood purifier obtained in this comparative example is a permselective hollow fiber membrane in the blood purifier after γ-irradiation. The elution amount of hydrogen peroxide was high, and the storage stability of the blood purifier was poor.

(Comparative Example 4)
In Comparative Example 1, the same procedure as in Comparative Example 1 was followed, except that washing of the selectively permeable hollow fiber membrane bundle was stopped and the wet hollow fiber membrane bundle was changed to dry in the same manner as in Comparative Example 3. Thus, a selectively permeable hollow fiber membrane bundle and a blood purifier were obtained. Tables 3 and 5 show the characteristics of the obtained selectively permeable hollow fiber membrane bundle and blood purifier. The amount of PVP elution was 18 ppm. The poor cleaning of the hollow fiber membrane was considered.

  In addition, the selectively permeable hollow fiber membrane bundle and blood purifier obtained in this Comparative Example were of lower quality than those of Comparative Example 3.

(Comparative Example 5)
In Comparative Example 1, the hollow fiber membrane bundle, the blood purifier, and the blood purification were the same as in Comparative Example 1 except that the combined use of the humectant was stopped during sterilization, and the blood purifier and the oxygen scavenger were sealed in the packaging bag. A container package was obtained. The relative humidity in the packaging bag was 35% RH. The characteristics of the obtained hollow fiber membrane bundle and blood purifier are shown in Tables 3 and 5. In the blood purifier obtained in Comparative Example 5, in addition to the problem of the blood purifier obtained in Comparative Example 1, the elution amount of hydrogen peroxide was increased by γ irradiation. Therefore, the storage stability of the blood purifier was also inferior, and the UV absorbance (220-350 nm) was also greatly deteriorated with the storage time. This is considered to be caused by the deterioration of the polyvinyl pyrrolidone in the hollow fiber membrane bundle due to the irradiation of γ rays because the humidity in the atmosphere around the hollow fiber membrane bundle at the time of γ ray irradiation is low.

(Comparative Example 6)
In Comparative Example 1, a hollow fiber membrane bundle, a blood purifier, and a blood purifier package were obtained in the same manner as in Comparative Example 1, except that the sealing of the oxygen scavenger in the packaging bag was stopped. The characteristics of the obtained hollow fiber membrane bundle and blood purifier are shown in Tables 3 and 5. The blood purifier obtained in Comparative Example 6 was of low quality, similar to the blood purifier obtained in Comparative Example 5. In this comparative example, since the oxygen scavenger was not enclosed, the oxygen concentration in the atmosphere around the hollow fiber membrane bundle at the time of γ-ray irradiation was not high and the oxidation was not suppressed. This is considered to be caused by the deterioration of polyvinylpyrrolidone in the membrane bundle.

(Example 2)
Polyethersulfone (Suika Chemtex Co., Ltd. Sumika Excel (registered trademark) 4800P) 1 part by mass, Polyvinylpyrrolidone (BASF Koridone (registered trademark) K-90) 0.10 parts by mass, DMAc 1.5 parts by mass are biaxial Kneading with a screw type kneader. The obtained kneaded material was put into a stirring type dissolution tank charged with 2.57 parts by mass of DMAc and 0.28 parts by mass of water, and stirred for 3 hours to dissolve. The kneading and dissolution were cooled so that the internal temperature did not rise above 30 ° C. Subsequently, the film forming solution was defoamed. The polyvinyl pyrrolidone having a hydrogen peroxide content of 100 ppm was used, and the supply tank in the raw material supply system and the dissolution tank were replaced with nitrogen gas. Further, the Froude number and the stirring Reynolds number at the time of dissolution were 1.1 and 120, respectively. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and simultaneously discharged together with a 55 mass% DMAc aqueous solution degassed as a hollow forming agent from a tube-in orifice nozzle heated to 55 ° C. After passing through a 300 mm dry section cut off from outside air by a tube, it was solidified in water at 60 ° C. The tube-in-orifice nozzle used had a central hole diameter of 90 μm, the draft ratio of the film forming solution was 1.06, and the absolute humidity of the dry part was 0.12 kg / kg dry air. The linear velocities immediately after discharge were 28560 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 5.9. All the water used in the spinning process was RO water. The specific resistance was 1.0 MΩcm. The hollow fiber membrane bundle pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. These guides and rollers were surface-treated with Teflon (registered trademark). Moreover, mist-like water was sprayed on the hollow fiber membrane bundle under running just before winding. A polyethylene film similar to that of Example 1 was wrapped around a bundle of about 10,000 hollow fiber membranes, and then washed by immersing twice in a 40 vol% isopropanol aqueous solution at 30 ° C. for 30 minutes.

  The obtained wet selective permeable hollow fiber membrane bundle was dried in the same manner as in Example 1. The moisture content of the dry selectively permeable hollow fiber membrane was 2.8% by mass. The obtained hollow fiber membrane had an inner diameter of 200.0 μm, a film thickness of 28.5 μm, and a content of polyvinyl pyrrolidone with respect to polyethersulfone was 3.3% by mass. Some of these manufacturing conditions are shown in Table 1.

  The hollow fiber membrane obtained in this example has a dense layer on the inner surface, and the dense layer comprises an aggregate of aggregated particles, the average particle diameter of the aggregated particles is 87 nm, and the particle diameter of the aggregated particles The standard deviation of the distribution was 20 nm (0.23 times the average particle diameter), and the maximum protrusion height (RV) of the inner surface was 0.12 μm.

  The obtained dry permselective hollow fiber membrane bundle was equally divided into 10 pieces in the longitudinal direction, and 1 g of the dry hollow fiber membrane bundle was weighed from each part, and the hydrogen peroxide elution amount was quantified. The hydrogen peroxide elution amount was stable at a low level in all parts, and the storage stability of the selectively permeable hollow fiber membrane bundle was excellent.

  A blood purifier was assembled using the hollow fiber membrane bundle thus obtained. As a result of the leak test, no adhesion failure caused by the sticking of the hollow fiber membranes was observed. The blood purifier is switched to a water release type (AGELESS Z-200PT (registered trademark) manufactured by Mitsubishi Gas Chemical Co., Inc.) as an oxygen scavenger, and the use of a humidity control agent is stopped, and the packaging bag is sealed and stored until sterilization. Sterilization was performed in the same manner as in Example 1 except that the time was 216 hours. When a selectively permeable hollow fiber membrane bundle was cut out from the blood purifier after γ-irradiation and subjected to the eluate test, the polyvinylpyrrolidone elution amount was 3 ppm, and the maximum hydrogen peroxide elution amount was 2 ppm. there were. In addition, the storage stability of the blood purifier obtained in this example is good, and the maximum UV (220-350 nm) absorbance, which is the approval standard for manufacturing a dialysis artificial kidney device for a hollow fiber membrane bundle after storage for one year. The value was 0.06, and the reference value of 0.1 or less was maintained. Further, when the permselective hollow fiber membrane bundle was taken out from the blood purifier and the outer surface was observed with a microscope, no defects such as scratches were observed. No blood cell leak was found in the blood leak test using bovine blood. Moreover, since the methylene blue adsorption rate has an appropriate value as in the blood purifier of Example 1, negative charge control is appropriate, and the methylene blue adsorption rate has an appropriate value. The control is appropriate, and as described above, the particle size of the aggregated particles of the inner dense layer, the standard deviation of the particle size distribution, and the smoothness of the surface are appropriate, and the selective separability and the stability over time are good. It was.

  In addition, the blood purifier has good water permeability at the time of priming, and is highly practical as a blood purifier.

  The evaluation results of the obtained selectively permeable hollow fiber membrane and blood purifier are shown in Tables 3 and 4.

(Comparative Example 7)
16% by mass of polyethersulfone (manufactured by Sumika Chemtex, Sumika Excel (registered trademark) 5200P), 5.4% by mass of polyvinylpyrrolidone (Collidon (registered trademark) K-90, manufactured by BASF), 75% dimethylacetamide (DMAc). 6% by mass and 3% by mass of water were directly charged into a dissolution tank having a stirrer and dissolved at 75 ° C. At this time, the dissolution fluid number and the stirring Reynolds number were 1.0 and 120, respectively. Subsequently, the film forming solution was defoamed. As the polyvinyl pyrrolidone, one having a hydrogen peroxide content of 450 ppm was used, and the supply tank in the raw material supply system and the dissolution tank were not replaced with nitrogen gas. This membrane-forming solution is passed through a 30 μm filter, and simultaneously discharged from a tube-in orifice nozzle heated to 60 ° C. using a 40 mass% DMAc aqueous solution at 50 ° C. previously degassed as a hollow forming agent. After passing through a 300 mm dry part cut off from the outside air, it was solidified in water at 60 ° C. with a concentration of 10% by mass. The tube-in-orifice nozzle used had a center hole diameter of 180 μm, a draft ratio of 2.41, and the absolute humidity of the dry section air was 0.18 kg / kg dry air. The linear velocities immediately after discharge were 55660 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 11.5. All water used in the spinning process was tap water. The obtained hollow fiber membrane bundle was passed through a 40 ° C. water washing tank for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up in a wet state and dried in the same manner as in Comparative Example 3. The obtained hollow fiber membrane bundle had an inner diameter of 200.2 μm and a film thickness of 28.5 μm. The selectively permeable hollow fiber membrane bundle obtained in this comparative example has a high level of elution amount of hydrogen peroxide and polyvinylpyrrolidone, and the amount of hydrogen peroxide elution amount varies greatly depending on the sampling location.

  Using the selectively permeable hollow fiber membrane bundle thus obtained, a blood purifier was assembled and sterilized by the same method as in Comparative Example 1. When the hollow fiber membrane bundle was cut out from the blood purifier and subjected to the eluate test, the polyvinylpyrrolidone elution amount was 17 ppm and the maximum hydrogen peroxide elution amount was 20 ppm. Since the permselective hollow fiber membrane bundle in the blood purifier obtained in this comparative example had a high hydrogen peroxide elution amount, the storage stability was poor. The blood purifier obtained in this comparative example cannot maintain the maximum value of UV (220-350 nm) absorbance, which is already a dialysis-type artificial kidney device manufacturing approval standard, after about 5 months of storage. It was. In the blood leak test using bovine blood, two of 30 blood purifiers had blood cell leaks. From the fact that the uneven thickness is small and the outer surface hole diameter is too large, it seems that pinholes are generated and / or broken. Moreover, blood compatibility was inferior. In addition, the blood purifier obtained in the comparative example was inferior in selective separation and stability over time. The hollow fiber membrane filled in the blood purifier obtained in this comparative example is not suitable for the film forming conditions, and the aggregate particle size of the dense layer on the inner surface of the hollow fiber membrane and the standard deviation of the particle size distribution are appropriate. In addition, the hollow fiber membrane bundle obtained in the comparative example has a high linear velocity ratio of 11.5 times immediately after discharge, excessive friction at the interface between the membrane forming solution and the hollow forming agent, and is moderate. The negative charge could not be controlled, and stable spinning could not be performed, so a uniform hollow fiber membrane could not be obtained, and it was considered that the contribution of the deterioration of the surface smoothness of the inner surface was significant. .

  These results are shown in Tables 3 and 6.

(Example 3)
In the same manner as in Example 2, 18% by mass of polysulfone (P-3500 manufactured by Amoco), 9% by mass of polyvinylpyrrolidone (Collidon (registered trademark) K-60 manufactured by BASF), 68% by mass of dimethylacetamide (DMAc), A film forming solution consisting of 5% by mass of water was prepared. As the polyvinyl pyrrolidone, one having a hydrogen peroxide content of 100 ppm was used. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and simultaneously with a 62 mass% DMAc aqueous solution at 45 ° C. that had been degassed in advance as a hollow forming agent from a tube-in orifice nozzle heated to 45 ° C. After discharging and passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in 50 ° C. water. The tube-in-orifice nozzle used had a center hole diameter of 100 μm, a draft ratio of 1.03, and an absolute humidity of the dry part of 0.12 kg / kg dry air. The linear velocities immediately after discharge were 17910 cm / min and 4840 cm / min, respectively, for the hollow forming agent and the film forming solution. The linear velocity ratio was 3.7. All the water used in the spinning process was RO water. The specific resistance was 1.0 MΩcm. The hollow fiber membrane pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. These guides and rollers were surface-treated with Teflon (registered trademark). Moreover, mist-like water was sprayed on the hollow fiber membrane bundle under running just before winding. A bundle of about 10,000 hollow fiber membranes was immersed in pure water and washed in an autoclave at 121 ° C. for 1 hour. A polyethylene film similar to that in Example 1 was wound around the hollow fiber membrane bundle after washing, and then dried in the same manner as in Example 1. The resulting hollow fiber membrane had an inner diameter of 201.2 μm and a film thickness of 44.0 μm. The water content was 2.3% by mass, and the content of polyvinyl pyrrolidone relative to polysulfone was 4.2% by mass. As is clear from Tables 3 and 4, the hydrogen peroxide elution amount was stable at a low level in all sites. Therefore, the storage stability of the selectively permeable hollow fiber membrane bundle was good. Some of these manufacturing conditions are shown in Table 1.

  Further, the hollow fiber membrane obtained in this example has a dense layer on the inner surface, and the dense layer is composed of aggregates of aggregated particles, and the average particle size of the aggregated particles is 55 nm. The standard deviation of the diameter distribution was 11 nm (0.20 times the average particle diameter), and the maximum protrusion height (RV) of the inner surface was 0.09 μm.

  A blood purifier was assembled in the same manner as in Example 1 using the selectively permeable hollow fiber membrane bundle thus obtained. After the RO side was filled with deoxygenated water having a dissolved oxygen concentration of 0.05 ppm obtained by passing RO water through the hollow fiber membrane type deaerator into the blood purifier, the blood side was filled at 200 ml / min for 5 minutes. The water content in the hollow fiber membrane was adjusted to 100 mass% by stopping and expelling the filling water with nitrogen gas at 60 ° C. at a pressure of 0.1 MPa and continuing the ventilation. The above operation was performed in a nitrogen atmosphere. The oxygen concentration in the blood purifier was 0.5% by volume. All the blood and dialysate inlets and outlets of the blood purifier dried in the environment are sealed with caps made of ethylene-propylene synthetic rubber, the outer layer is a biaxially stretched polyamide film with a thickness of 25 μm, and the inner layer is unstretched with a thickness of 50 μm. It sealed in the packaging bag which consists of a laminated body of a polyethylene film.

  After sealing and storing at room temperature for 120 hours, 25 kGy of γ rays were irradiated. When the hollow fiber membrane bundle was cut out from the blood purifier and subjected to the eluate test, the polyvinylpyrrolidone elution amount was 4 ppm, and the maximum hydrogen peroxide elution amount was 3 ppm, which was a satisfactory level. Therefore, the storage stability of the blood purifier obtained in this example is good, and UV is the approval standard for the manufacture of a dialysis artificial kidney device for a selectively permeable hollow fiber membrane bundle in the blood purifier after storage for one year. The maximum value of (220-350 nm) absorbance was 0.05, and the reference value of 0.1 or less was maintained. Further, when the hollow fiber membrane bundle was taken out from the blood purifier and the outer surface was observed with a microscope, defects such as scratches were not observed. In addition, citrated fresh cow blood was flowed to the blood purifier at a blood flow rate of 300 mL / min and a filtration rate of 90 mL / min, but no blood cell leak was observed. As a result of the leak test, no adhesion failure caused by the sticking of the hollow fibers was found. Further, like the blood purifier of Example 1, the smoothness of the inner surface is good, and the methylene blue adsorption rate has an appropriate value. Therefore, negative charge control is appropriate, and As described above, the particle size of the aggregated particles of the inner dense layer, the standard deviation of the particle size distribution, and the smoothness of the surface were appropriate, and the selective separability and the stability over time were good.

  In addition, the blood purifier has good water permeability at the time of priming, and is highly practical as a blood purifier.

  Tables 3 and 4 show the evaluation results of the selectively permeable hollow fiber membranes and blood purifiers obtained in the above Examples.

(Comparative Example 8)
In Example 3, the hollow fiber membrane bundle and blood purifier of Comparative Example 8 were obtained in the same manner as in Example 3 except that the following changes were made.
(1) Change the nozzle temperature to 65 ° C., (2) change the center hole diameter of the nozzle to 180 μm, (3) change the hollow forming agent discharge linear velocity to 55660 cm / min, and set the linear velocity ratio to 11.5. (4) The dry part length is 600 mm, (5) the DMAC concentration in the hollow forming agent is 35% by mass, (6) the draft ratio is 2.45, (7) all the water used in the spinning process is tap water, 8) It changed so that the static elimination process at the time of the loading operation | work of the hollow fiber membrane bundle to a blood purifier container might be abbreviate | omitted. Some of these manufacturing conditions are shown in Table 2. The evaluation results of the hollow fiber membrane and the blood purifier are shown in Tables 3 and 6, respectively.
The hollow fiber membrane filled in the blood purifier obtained in this comparative example is not suitable for its membrane formation condition, and the standard deviation of the particle size of the dense particles and the particle size distribution of the dense layer inside the hollow fiber membrane In addition, the hollow fiber membrane bundle obtained in this comparative example has a high ratio of linear velocity immediately after discharge of 11.5 times, and the friction at the interface between the membrane forming solution and the hollow forming agent is excessive. In addition, it was impossible to control to a moderate negative charge, and because stable spinning could not be performed, a uniform hollow fiber membrane could not be obtained, and the contribution of the deterioration of the surface smoothness of the inner surface was great. Conceivable.

(Comparative Example 9)
The method of Comparative Example 8 was sterilized in the same manner as in Comparative Example 8 except that the sealing plug was changed to be removed. The results are shown in Tables 3 and 6. The blood purifier obtained in this comparative example is not hermetically sealed in addition to the problem of the blood purifier obtained in comparative example 8, so that air enters the blood purifier and the hollow fiber is irradiated during γ-ray irradiation. Since the circumference of the membrane bundle is filled with air and oxygen gas is dissolved in the water in the hollow fiber membrane, the effect of suppressing the degradation of polyvinylpyrrolidone due to the γ-ray irradiation by the moisture in the hollow fiber membrane is reduced. The amount of elution of hydrogen peroxide was increased by irradiation. Therefore, long-term storage stability of the blood purifier deteriorated.

(Comparative Example 10)
In the method of Comparative Example 8, except that the water charged in the assembled blood purifier was changed to use RO water having a dissolved oxygen amount of 8 ppm without degassing, and the storage time until sterilization was 40 hours, Sterilization was performed in the same manner as in Comparative Example 8. The results are shown in Tables 3 and 6. In addition to the problem of the blood purifier obtained in Comparative Example 8, the blood purifier obtained in this comparative example is not deoxygenated in the water that exists in the selectively permeable hollow fiber membrane. As a result, the hollow fiber membrane deteriorated and the amount of hydrogen peroxide eluted increased. For this reason, the storage stability of the blood purifier was poor.

(Comparative Example 11)
In the method of Comparative Example 8, except that the removal of deaerated water filled in the assembled blood purifier and the moisture content adjustment in the hollow fiber membrane were changed to dry air, and the storage time until sterilization was 216 hours, The blood purifier was assembled and sterilized in the same manner as in Comparative Example 8. The oxygen concentration in the blood purifier was 21% by volume. The results are shown in Tables 3 and 6. The blood purifier obtained in this comparative example was worse in quality than the blood purifier obtained in comparative example 8.

(Comparative Example 12)
In the method of Comparative Example 8, the moisture content of the selectively permeable hollow fiber membrane is not adjusted, and the moisture content remains in the state of 2.3% by mass (that is, the state where the deaerated water is not charged and driven off). A blood purifier was obtained in the same manner as in Comparative Example 8, except that the γ-ray irradiation was changed. In addition to the problem of the blood purifier obtained in Comparative Example 8, the blood purifier obtained in this comparative example is a hollow fiber membrane in which polyvinylpyrrolidone in the selectively permeable hollow fiber membrane loaded in the blood purifier is Due to the low water content, the crosslinking of polyvinylpyrrolidone did not proceed. Therefore, the amount of polyvinylpyrrolidone eluted was large and the quality was low. Moreover, since the moisture content in the hollow fiber membrane was low, the degradation reaction of polyvinylpyrrolidone was increased by γ-ray irradiation, and the hydrogen peroxide elution amount was increased. Therefore, the storage stability of the blood purifier was not good.

Example 4
In the same manner as in Example 2, 17% by mass of polysulfone (Amoco P-1700), 5% by mass of polyvinylpyrrolidone (BASF Kollidon (registered trademark) K-60), 73% by mass of dimethylacetamide (DMAc), A film forming solution consisting of 5% by mass of water was prepared. As the polyvinyl pyrrolidone, one having a hydrogen peroxide content of 120 ppm was used. The obtained film-forming solution was passed through a two-stage filter of 15 μm and 15 μm, and simultaneously with a 58 mass% DMAc aqueous solution at 50 ° C. degassed as a hollow forming agent from a tube-in orifice nozzle heated to 45 ° C. After discharging and passing through a 600 mm air gap portion cut off from the outside air by a spinning tube, it was solidified in 50 ° C. water. The tube-in orifice nozzle used had a central hole diameter of 100 μm, the absolute humidity of the dry part was 0.12 kg / kg dry air, and the draft ratio was 1.01. The hollow fiber membrane bundle pulled up from the coagulation bath was passed through a water washing tank at 85 ° C. for 45 seconds to remove the solvent and excess polyvinylpyrrolidone, and then wound up. The roller for changing the yarn path during the spinning process was a mirror-finished surface, and the fixing guide was a satin-finished surface. These guides and rollers were surface-treated with Teflon (registered trademark). Moreover, mist-like water was sprayed on the hollow fiber membrane bundle under running just before winding. About 10,000 bundles of the hollow fiber membranes were immersed in pure water, washed in an autoclave at 121 ° C. for 1 hour, and dried in the same manner as in Example 1. The water content was 3.8% by mass.

  The highest temperature reached of the hollow fiber membrane bundle during the drying process was 56 ° C. The obtained selectively permeable hollow fiber membrane bundle had an inner diameter of 200.0 μm and a film thickness of 45.2 μm. As is apparent from Table 3, the hydrogen peroxide elution amount was stable at a low level in all parts, and the storage stability of the selectively permeable hollow fiber membrane was excellent.

  Further, the hollow fiber membrane obtained in this example has a dense layer on the inner surface, and the dense layer is composed of aggregates of aggregated particles, the average particle diameter of the aggregated particles is 60 nm, and the particles of the aggregated particles The standard deviation of the diameter distribution was 20 nm (0.33 times the average particle diameter), and the maximum protrusion height (RV) of the inner surface was 0.15 μm.

  A blood purifier was assembled in the same manner as in Example 1 using the selectively permeable hollow fiber membrane bundle thus obtained. Nitrogen was bubbled through deoxygenated water having a dissolved oxygen concentration of 0.05 ppm by passing RO water through a hollow fiber membrane deaerator to prepare nitrogen-saturated water. After filling the blood side of the blood purifier with 200 ml / min for 5 minutes with this nitrogen-saturated water, the blood side was stopped, the filling water was expelled with 60 ° C. air at a pressure of 0.1 MPa, and the ventilation was continued. Thus, the water content in the hollow fiber membrane was adjusted to 10% by mass. All the blood and dialysate inlets and outlets of the blood purifier dried under these conditions are sealed with a cap made of ethylene-propylene synthetic rubber, a biaxially stretched polyamide film having an outer layer thickness of 25 μm and an unstretched polyethylene having an inner layer thickness of 50 μm. It sealed in the packaging bag which consists of a laminated body of a film. 50 hours after sealing, it was changed to γ-rays and sterilized by irradiation with an electron beam using an electron beam irradiation machine having an acceleration voltage of 5000 KV.

  As a result of conducting a leak test of the obtained blood purifier, no adhesion failure caused by the sticking of the hollow fiber membranes was observed. When the hollow fiber membrane bundle was cut out from the sterilized blood purifier and subjected to the eluate test, the polyvinylpyrrolidone elution amount was 5 ppm and the maximum hydrogen peroxide elution amount was 3 ppm, which was a satisfactory level. Therefore, the storage stability of the blood purifier obtained in this example is good, and UV is the approval standard for the manufacture of a dialysis artificial kidney device for a selectively permeable hollow fiber membrane bundle in the blood purifier after storage for one year. The maximum value of (220-350 nm) absorbance was 0.06, and the reference value of 0.10 or less was maintained. Further, when the hollow fiber membrane bundle was taken out from the blood purifier and the outer surface was observed with a microscope, defects such as scratches were not observed. In addition, citrated fresh cow blood was flowed to the blood purifier at a blood flow rate of 200 mL / min and a filtration rate of 50 mL / min, but no blood cell leak was observed. Further, like the blood purifier of Example 1, the smoothness of the inner surface is good, and the methylene blue adsorption rate has an appropriate value. Therefore, negative charge control is appropriate, and As described above, the particle size of the aggregated particles of the inner dense layer, the standard deviation of the particle size distribution, and the smoothness of the surface were appropriate, and the selective membrane separation property and the stability over time were good.

  In addition, the blood purifier has good water permeability at the time of priming, and is highly practical as a blood purifier.

  The evaluation results are shown in Tables 3 and 4.

(Examples 5 and 6)
In the method of Example 3, selective permeation was carried out in the same manner as in Example 3 except that after sealing and after leaving for 24 hours and 40 hours at room temperature, γ-ray irradiation was performed under the same conditions as in Example 3. A hollow fiber membrane and a blood purifier were obtained. These characteristics are shown in Tables 3 and 4.
In the selectively permeable hollow fiber membrane and blood purifier obtained in this example, the degradation reaction of the hollow fiber membrane is suppressed, the methylene blue adsorption rate has an appropriate value, and negative charge control is appropriate. Yes, the particle size of the agglomerated particles of the inner dense layer, the standard deviation of the particle size distribution and the smoothness of the surface are appropriate, the separation characteristics are stable over time, and the storage stability is also excellent. However, since the time from sealing to γ-ray treatment is short, the blood purifier obtained in Example 3 is slightly inferior in the performance of water permeability at the time of priming. It was shown that the elapsed time until irradiation was affected on the performance.

  Conventionally, no quality control method focusing on the behavior of hydrogen peroxide in a hollow fiber membrane bundle has been known at all. The quality of the hollow fiber membrane bundle can be examined from many viewpoints. For example, the hollow fiber membrane bundle is cut into 27 cm in the longitudinal direction, and is divided into 10 equal intervals of 2.7 cm. Measure the elution amount of hydrogen peroxide at each site. A difference A is determined based on the maximum and minimum elution amounts. And an average elution amount is calculated by averaging it. Further, the maximum value B of the difference between the maximum elution amount or the minimum elution amount and the average elution amount is set as the degree of quality variation. FIG. 2 shows a variation state of the first embodiment. In the case of Comparative Example 3, it can be obtained similarly. The values calculated in this way are summarized in Table 3.

  The relationship between the hydrogen peroxide elution amount (maximum value) from the hollow fiber membrane bundle and the quality variation degree (maximum average elution amount difference) of the hollow fiber membrane bundle is plotted in FIG. As the amount of hydrogen peroxide eluted increases, the difference in the amount of hydrogen peroxide eluted from each part of the hollow fiber membrane bundle divided into 10 parts tends to increase. Variation in the elution amount of hydrogen peroxide in the hollow fiber membrane bundle affects the performance and function of the hollow fiber membrane, which is not preferable for quality control. If the maximum elution amount of hydrogen peroxide is 5 ppm or less, it is critical in terms of suppressing variations in the elution amount of hydrogen peroxide and maintaining the stability of the hollow fiber membrane bundle and blood purifier during long-term storage. It can be seen that there is significant significance.

  FIG. 4 shows blood filled with a hollow fiber membrane bundle in which the amount of polyvinylpyrrolidone eluted from the hollow fiber membrane bundle is suppressed to 10 ppm or less and the amount of hydrogen peroxide from the hollow fiber membrane bundle is suppressed to 5 ppm or less. The behavior of UV absorbance when the purifier is stored for one year is shown. Those whose hydrogen peroxide elution amount is suppressed to 5 ppm or less can suppress the UV absorbance to 0.1 or less even after long-term storage, so the hydrogen peroxide elution amount from the hollow fiber membrane bundle is 5 ppm or less. It can be said that the suppression significantly contributes to the stability of the quality of the blood purifier.

  Since the blood purifier of the present invention is of a dry type, it has advantages such as being light, not freezing, and difficult to propagate various germs. In addition, the blood purifier of the present invention has the advantages of having high water permeability in blood purification treatment for removing a large amount of water, excellent selective separation, and little change with time in the performance, HDFIII-b type It has the feature that it can be adapted as a blood purifier. In addition, since the radical scavenger is not included, there is an advantage that when it is used for blood purification, an operation for washing and removing the radical scavenger in advance is unnecessary. Furthermore, in the present invention, even in the dry state and in the absence of a radical scavenger, even if irradiated with radiation, the effect of the conventional technique that the deterioration of the selectively permeable hollow fiber membrane due to irradiation is suppressed is not achieved Therefore, the production of hydrogen peroxide due to the deterioration reaction is small, and the blood purifier of the present invention has the advantage of excellent long-term storage stability. For example, the polysulfone-based permselective hollow fiber membrane loaded in the blood purifier suppresses the generation of hydrogen peroxide even when irradiated with radiation, such as polyvinylpyrrolidone caused by the hydrogen peroxide. Therefore, even if the blood purifier is stored for a long period of time, the maximum value of UV (220-350 nm) absorbance, which is the dialysis-type artificial kidney device manufacturing approval standard, can be maintained at 0.10 or less. There is an advantage that safety can be secured when the purifier is stored for a long period of time. Therefore, it is important to contribute to the industry.

It is sectional drawing of a blood purifier. It is a schematic diagram which shows the hydrogen peroxide elution amount of each site | part when a hollow fiber membrane is divided into 10 equal parts. It is a schematic diagram which shows the variation degree of the quality in a hollow fiber membrane bundle. It is a schematic diagram which shows the change of UV light absorbency during the preservation | save period of a blood purifier.

Explanation of symbols

1: Blood purifier 2: Housing 3: Hollow fiber membrane bundle 4: Adhesive resin 5: Cap 6a: Dialysate inlet 6b: Dialysate outlet 7a: Blood inlet 7b: Blood outlet

Claims (5)

The blood contact surface has a dense layer, and the dense layer is an aggregate of aggregated particles having a diameter of 55 to 150 nm, and the maximum protrusion height (PV value) of the blood contact surface is 0.09 μm or more and 0.3 μm or less. A hematocrit (Ht) 40 ± 2 was placed in a blood purifier filled with a polysulfone-based permselective hollow fiber membrane bundle containing polyvinylpyrrolidone so as to have a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard). When the bovine blood adjusted to 0.0% and total protein concentration 6.5 ± 0.5 g / dl was flowed at 300 ml / min and filtration rate 90 ml / min, β2-micro at 15 minutes and 120 minutes after the start of blood filtration. the sieving coefficient of globulin, when the SCβ2MG (15 min) and SCβ2MG (120 min), respectively, SCβ2MG (120 min) / SCβ2MG (15 minutes) is ≧ 0.6, SCβ2 G is a (120 min) ≧ 0.71, by dividing the hollow fiber membrane bundle into 10 in the longitudinal direction, when the test was carried out defined for Dialysis-type Artificial Kidney Apparatus approval criteria for each site, resulting A polysulfone-based hollow fiber membrane hemodiafiltration machine in which the extracted solution has a hydrogen peroxide elution amount of 5 ppm or less at all sites. The polysulfone-based hollow fiber membrane hemodialysis filter according to claim 1, wherein the amount of polyvinylpyrrolidone eluted from the hollow fiber membrane is 10 ppm or less. The polysulfone-based hollow fiber membrane hemodialysis filter according to claim 1 or 2 , wherein a standard deviation value of a particle size distribution of the aggregated particles forming the dense layer is less than 0.5 times an average value. . The polysulfone-based hollow fiber membrane hemodialysis filter according to any one of claims 1 to 3 , wherein the hollow fiber membrane has an adsorption rate of methylene blue of 40% or more and 80% or less. To a blood purifier with a membrane area of 1.5 m ² (based on the inner diameter of the hollow fiber membrane), 300 ml / ml of bovine blood adjusted to a hematocrit (Ht) of 40 ± 2.0% and a total protein concentration of 6.5 ± 0.5 g / dl. The polysulfone-based hollow according to any one of claims 1 to 4 , wherein the sieving coefficient of bovine serum albumin is 15 or less 15 minutes after the start of blood filtration at a filtration rate of 90 ml / min. Yarn type hemodiafiltration machine.

Images